Mesenchymal stem cell-mediated transfer of mitochondria: mechanisms and functional impact

Francesca Velarde; Sarah Ezquerra; Xavier Delbruyere; Andres Caicedo; Yessia Hidalgo; Maroun Khoury

doi:10.1007/s00018-022-04207-3

. 2022 Mar 5;79(3):177. doi: 10.1007/s00018-022-04207-3

Mesenchymal stem cell-mediated transfer of mitochondria: mechanisms and functional impact

Francesca Velarde ^1,^2,^3,⁸, Sarah Ezquerra ^1,^2,³, Xavier Delbruyere ^1,^2,³, Andres Caicedo ^4,^5,^6,⁷, Yessia Hidalgo ^1,^2,^3,^✉, Maroun Khoury ^1,^2,^3,^✉

PMCID: PMC11073024 PMID: 35247083

Abstract

There is a steadily growing interest in the use of mitochondria as therapeutic agents. The use of mitochondria derived from mesenchymal stem/stromal cells (MSCs) for therapeutic purposes represents an innovative approach to treat many diseases (immune deregulation, inflammation-related disorders, wound healing, ischemic events, and aging) with an increasing amount of promising evidence, ranging from preclinical to clinical research. Furthermore, the eventual reversal, induced by the intercellular mitochondrial transfer, of the metabolic and pro-inflammatory profile, opens new avenues to the understanding of diseases’ etiology, their relation to both systemic and local risk factors, and also leads to new therapeutic tools for the control of inflammatory and degenerative diseases. To this end, we illustrate in this review, the triggers and mechanisms behind the transfer of mitochondria employed by MSCs and the underlying benefits as well as the possible adverse effects of MSCs mitochondrial exchange. We relay the rationale and opportunities for the use of these organelles in the clinic as cell-based product.

Keywords: Mitochondria, Mesenchymal stem/stromal cells, Mitochondrial transfer, Cell-based therapy

High road for MSCs’ translational avenues

Human mesenchymal stem/stromal cells (MSCs) are members of non-hematopoietic adult stem cells that originate from the mesoderm and can be found in almost all tissues [1]. In fact, they have been successfully isolated and expanded in vitro from the fetal liver, muscle, bone marrow, adipose tissue, and the umbilical cord. These cells possess the ability to differentiate while maintaining their stemness (self-renewal) and the ability to give rise to differentiated cell types into mesoderm lineages, such as osteocytes, adipocytes, chondrocytes, ectodermic cells and endodermic cells (multilineage differentiation) [2] MSCs possess a versatile range of therapeutic applications due to their capacity for multilineage differentiation and therapeutical effects, such as anti-apoptotic [3, 4], anti-inflammatory [5–7], immunomodulatory [5, 8, 9], and oxidative stress regulators [10], on different target cells (Fig. 1). For instance, they can act on metabolism through the secretion of chemokines, growth factors, cytokines and the production of many secretomes and proteomes, which is important when mediating hematopoietic stem cells (HSCs) engraftment, MSCs differentiation, regulation of angiogenesis and apoptosis [9, 11]. Nonetheless, not only the direct interaction of these cells has shown to exert benefits. As shown by Kinnaird et al., MSCs-conditioned media stimulated in vitro proliferation and migration of endothelial cells. While in in vivo experiments with mice that had undergone hindlimb ischemia, the sole injection of MSCs-conditioned media was sufficient to allow regeneration of the blood flow on the target limb [12]. Multiple research groups have shown that MSCs contributed to the recovery of tissues in models for cardiovascular, lung, spinal cord injuries, autoimmune, liver, bone and cartilage diseases, such as stroke [13], myocardial infarction [14], limb ischemia [15], meniscus injury osteoarthritis [16, 17], acute lung injury [18], and graft versus host diseases [19, 20].

Fig. 1 — Comparative biological impact between MSCs and MSC-derived mitochondria on target cells. Immunomodulation by MSC, involves a paracrine secretion of factors such as indoleamine 2,3-dioxygenase (IDO), transforming growth factor beta (TGF-β) and histocompatibility locus antigen G (HLA-G5), promoting inhibition of T cell proliferation. In addition, transfer or MSC-derived mitochondria has shown to induce regulatory T cells (Treg) differentiation, the involved mechanisms and pathways are still to be unraveled. MSCs exert anti-inflammatory effects also by the secretion of factors, such as prostaglandin E2 (PGE2) and tumor necrosis factor-stimulated gene 6 (TSG-6). PGE2 secreted by MSCs bind to EP2 and EP4 receptors expressed by macrophage inducing cyclic AMP upregulation (cAMP) promoting polarization to M2 phenotype. TSG-6 secreted by MSC inhibits activation of M1 macrophages. Mechanisms and pathways of anti-inflammatory effects from mitochondrial transfer are yet to be confirmed. The anti-apoptotic effect of MSCs is due to the enhancement of B cell lymphoma 2 (Bcl-2) expression. Likewise mitochondrial transfer also has anti-apoptotic effects in target cells, by increased expression of Bcl-2 and reduced activity of Bcl-2-associated X (Bax) and Caspase-3 (Casp3) (unpublished data). MSCs have shown the ability to regulate oxidative stress by increasing levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Similarly mitochondrial transfer exhibits oxidative stress regulation by the enhanced expression of mitochondrial superoxide dismutase 2 (SOD-2)

Mesenchymal stem/stromal: a frontliner in cell therapy

MSCs have shown remarkable tissue repair and regenerative properties. MSCs are activated by damage signals or inflammatory patterns, causing them to migrate to the affected tissue and promote its repair [21]. It has been observed that once MSCs are in the damaged site, they attract cells, such as macrophages, keratinocytes and endothelial cells to help the wounded tissue to heal [22]. MSCs are well known for their capacity to regulate or suppress the immune response, enabling tissue reconstitution after damage. These cells have the ability to form connections with tissue resident cells by transferring intracellular factors and organelles modifying the damaged phenotype to somatic cells or by inducing an anti-inflammatory response in immune cells [18, 23–25]. MSCs produce cytokines and growth factors, release extracellular vesicles (EVs) containing a regenerative cocktail of transcription factors, mRNAs, microRNAs, and even mitochondria, thus revitalizing the recipient cells. Among the regenerative properties of MSCs, they can fuse with injured cells, such as cardiac and brain cells. Huda and colleagues were able to show neuronal rescue of injected fetal MSCs in the cerebella of symptomatic aged mice, which selectively fuse with injured Purkinje cells and interneurons but, interestingly, not with healthy neurons [26, 27]. Research on MSCs has shown their immense potential in cell therapy and how mimicking or replicating their properties artificially such as through the transfer of mitochondria from MSCs to other cells, could lead to new regenerative applications. Among the most striking paracrine properties of MSCs is mitochondrial transfer. This transfer of mitochondria to damaged cells has inspired the development of new therapies to treat harmed tissue, especially after heart ischemia [28, 29]. The reparative effects of artificial mitochondria transfer were first evidenced in vitro by Clark and Shay in 1989 [30]. In this seminal study, the authors demonstrated that purified mitochondria from antibiotic-resistant cell lines could be transferred to antibiotic sensitive mammalian cell lines, not only these cells internalized the mitochondria via endocytosis, but also acquired the donor cell antibiotic resistance [30]. Later, this process was observed to occur naturally among cells. Cell types, such as PC12, fibroblasts and especially MSCs, are able to transfer mitochondria to damaged cells and tissue [31–35]. These preclinical results paved the way for current and ongoing clinical trials that use not only cellular components, but also the secretome of MSCs.

Traditionally, cell therapy implies the transfer of cells, both intact and alive, into a patient to recover tissue loss of function, delay the progression of symptoms, decrease the severity of a disease, or cure it. MSCs are the most tested and used cells for cell therapy. They were first described 30 years ago, with over more than 55,000 publications available today [36]. About 1000 clinical trials are registered for MSCs (ClinicalTrials.gov) with ten studies in phase 4, showing promising results, especially for treating osteoarthritis and heart ischemia [37, 38]. Even when the use of MSCs for cell therapy is moving forward, important challenges need to be overcome, such as reporting clinical trials results, detailed protocols that include methods of isolation and expansion, effects of the MSCs and adverse events [39, 40]. Nowadays, this therapy has extended the application from unmanipulated cells to those being modified or conditioned ex vivo, such as shown by Kurte et al., using bacterial lipopolysaccharide (LPS)-conditioned MSCs in an experimental autoimmune encephalomyelitis mice model. Exposure to LPS at different times induces distinct phenotypes of MSCs, affecting their immunoplasticity [41].

MSCs can be isolated and expanded from many tissues, including extraembryonic and adult tissues [42] (Fig. 2). Extraembryonic tissue MSCs come from the umbilical cord (UC-MSCs), umbilical cord blood (UCB-MSCs), amniotic membrane (AM-MSCs), chorionic plate (CP-MSCs) and decidua parietalis (DP-MSCs) [42–44]. While adult tissue MSCs are commonly isolated from the bone marrow (BM-MSCs) and adipose tissue (AT-MSCs) [45–47]. Extraembryonic and adult MSCs show common properties, such as their capacity to adhere to plastic culture surfaces, differentiation potential (osteogenic, chondrogenic and adipogenic) and expression of extracellular markers such as CD105, CD90 and CD73. However, MSCs’ tissue of origin has an important influence on their proliferative and immune-regulatory capacity, affecting their application potential in medicine. For instance, it has been shown that UC-MSCs secrete higher levels of paracrine factors such as insulin-like growth factor-1 (IGF-1) when compared to AM-MSCs and CP-MSCs [48, 49]. In addition, extraembryonic MSCs can produce high concentrations of cytokines and growth factors, such as fibroblast growth factor (FGF), human angiopoietin-1 (Ang-1), transforming growth factor beta 1 (TGF-β1), VCAM-1, VCAM, hepatocyte growth factor (HGF), and interleukin-6 (IL-6) [48–50]. Among all the possible sources of MSCs, those derived from UC blood or Wharton’s Jelly (WJ) have a higher proliferative rate than BM-MSCs and AT-MSCs [51]. WJ-MSCs have advantages including proliferation, differentiation, telomerase activity, and clonogenic potential when compared to BM-MSCs, making them more suitable for clinical applications following good manufacturing practices [46].

The umbilical cord was the dominant source of MSCs in all clinical trials until 2017 [40]. UC-MSCs are being used in 40 clinical trials to treat 13 neurological conditions, such as autism, amyotrophic lateral sclerosis, ataxia, and cerebral palsy. Twenty-three clinical trials were performed with UC-MSCs to treat immunologic disorders including: systemic lupus erythematosus, hemorrhagic cystitis, HIV infection, rheumatoid arthritis and ulcerative colitis. Caritstem^®, produced in 2011 by Medipost in Korea, was the first marketable approved UC-MSCs’ allogeneic product to treat traumatic and degenerative osteoarthritis [52]. The second product to obtain commercial authorization was HeartiCellgram^®, made by the Korean company Pharmicell; this product is based on the application of autologous BM-MSCs to treat myocardial infarction [53]. The Canadian Osiris Therapeutics achieved the conditioned approval for the commercialization of Prochymal^® (Remestemcel-L) in 2012. Prochymal^® was based on BM-MSCs isolated from adult donors to treat allogenically graft versus host disease (GVHD) patients unresponsive to steroids [52]. However, Prochymal^® failed to show effectiveness against the placebo in phase III clinical trials. The same year, South Korea’s Food and Drug Administration approved Cupistem^® (Anterogen), a therapy based on the use of autologous AT-MSCs to treat Crohn’s Fistula (NCT04612465) [52]. In 2015, TEMCELL^® was used as an off-the-shelf product to treat acute GVHD. It contained BM-MSCs isolated and expanded from healthy adult donors. TEMCELL^® received the approval for commercialization by the Japanese Ministry of Health, Labor and Welfare and later by the New Zealand and Canada regulatory agencies [52, 54].

A further step into potential therapies not only considers intact or modified cells, but also subcellular components as well, among them mitochondria [34, 55] (Fig. 2). Clinical approaches and applications for MSCs have focused on direct cell-mediated action and environmental changes via the release of soluble factors or cellular compartments. Indeed, the MSCs secretome has also shown promising results for therapy. Among the multiple release molecules and substances, MSCs can secrete EVs from various sizes [56, 57]. For instance, small EVs (sEVs) act as intercellular mediators between MSCs and niche cells. Similarly, to MSCs, sEVs possess therapeutical capabilities, such as immunomodulatory [57] and angiogenic potential [58]. Promising results in preclinical studies paved the way for current ongoing clinical trials, for several diseases. Nonetheless, the main hurdles for the use of sEVS in the clinic are: (1) optimal culture conditions and protocols for the production, isolation, and storage of exosomes, to provide homogenous batches; (2) optimal dose and dosage for the administration of exosomes into patients; and (3) development of functional assays to evaluate the efficacy of in several conditions and diseases [59, 60]. There are over 90 clinical trials registered involving sEVs but only four evaluating MSC-derived. For instance, in a phase II/III clinical trial, two injections of UC-derived sEVs have shown to improve clinical outcomes in chronic kidney disease, such as eGFR levels and/or serum creatinine [61]. Currently, clinical trials are evaluating the effects of multiple intravenous infusions of UC blood-derived MSC sEVs in diabetes mellitus (type 1) based on preclinical data on mouse models that showed MSC-derived sEVs to increase the regulatory T cells (Treg) population in the spleen and regenerate pancreatic islets (NCT02138331). Other clinical trials using MSC sEVs are studying the effect of these vesicles on macular degeneration and ischemic stroke [57].

On the other hand, organelle-derived therapy has also seen a surge in clinical trials due to its success in preclinical studies mainly in mitochondrial diseases and infertility. Recently, trials for a new therapy, labeled as Mitochondrial Augmentation Therapy (MAT) are being held in different diseases. MAT is based on the ability of exogenous mitochondria to enter cells while in culture [62, 63]. MAT has been tested in Pearson Syndrome (PS) and Kearns–Sayre syndrome (KSS). Evidence has shown that in PS, a rare disorder affecting the bone marrow and exocrine pancreas, MAT enriches HSCs with healthy mitochondria before transplantation and improves aerobic capacity, mitochondrial membrane potential and HSCs overall function in PS cells in vitro. MAT therapy was developed by Minovia Therapeutics that is currently undergoing an open-label study (NCT03384420) to assess the safety and therapeutical effects. On the same note, MAT treatment on KSS patients has shown to improve clinical parameters, such as weight, dexterity, sitting independently, locomotion, and cognitive functions (improve speech and decrease seizures). At the cellular level, MAT in KS appears to increase peripheral blood lymphocytes and ATP content [62, 64]. Mitochondrial donation has also been assessed for fertility treatments. Currently, there is one clinical trial studying the effects of mitochondrial donation on fetal and postnatal development of children conceived using in vitro fertilization mitochondrial donation (NCT04113447). Even though many questions remain unanswered regarding the use of mitochondrial transfer for clinical applications; results from preclinical research support phase I/II clinical trials. The full effects of the mitochondrial transfer from MSCs, or other cell types such as cardiomyocytes [65] and adipocytes [66, 67], to injured or immunes cells, remain to be determined.

Mitochondrial transfer: more than just energy transfer

The therapeutic function of MSCs is achieved through cell-to-cell contact-dependent and independent mechanisms, including the release of paracrine factors, such as soluble molecules and EVs [5–10]. However, numerous studies have also shown that MSCs have the ability to replace defective mitochondria and compensate their malfunction through an exchange of cell-to-cell mitochondria, known as mitochondrial transfer between MSCs and target cells [68, 69]. In a pioneering experiment by Spees et al., mitochondrial exchange and its functional effects were demonstrated when A549 ρ° cells with mitochondrial DNA (mtDNA) defects were cocultured with human MSCs and acquired functional mitochondria. A549 ρ° cells increased oxygen consumption, and intracellular ATP levels, as well as membrane potential [35, 69]. The mitochondrial transfer was also demonstrated to rescue the growth of mitochondrial deficient cancer cells by the transfer of their healthy mitochondria, reestablishing the mitochondrial network of the receptor cell [35]. Furthermore, mitochondrial transfer can sustain the growth of cancer cells by allowing macromolecular biosynthesis and the fulfillment of bioenergetic requirements of high-proliferating cells [70].

From these antecedents, the mitochondrial transfer has been widely studied in different tissues, cells and models. For instance, in vivo exchange was established in an airway disease model, where the intra-tracheal administration of MSCs was associated with mitochondrial transfer to alveolar epithelium, increasing metabolic activity and improving lung damage and disease outcome in the treated animals [71]. Jackson et al. showed that MSCs-derived mitochondrial transfer from BM-MSCs to alveolar macrophages resulted in an increase in phagocytic activity and bioenergetics. These results revealed an antimicrobial effect of MSCs, by enhancing the effector functions of macrophages, in preclinical models of Acute Respiratory Distress Syndrome (ARDS) [25]. Recently, our group also showed that the transfer of mitochondria can lead to cell fate changes in immune cells. Indeed, the transfer of MSCs-derived mitochondria to T lymphocytes induced a highly suppressive CD25⁺FoxP3⁺ Treg population [72]. Furthermore, this effect was proven to be cell source-specific, as the changes in cell fate were abrogated when fibroblast or peripheral blood mononuclear cells (PBMCs)-derived mitochondria was used [72].

Interestingly, it is possible that under different stimuli, MSCs favor mitochondrial transfer. It has been described that to control intracellular oxidative stress MSCs can shed depolarized mitochondria, which are engulfed by macrophages [73], showing that oxidative stress is a stimulus to release mitochondria. In a more general context, it is reported that under inflammatory conditions monocytes [74] or platelets [75] release mitochondria, suggesting that inflammation could favor the mitochondrial transfer by MSCs, at least transfer via vesicles [76]. On the same note, increased mitochondrial transfer from stromal cells to HSCs was observed when mice were treated with LPS, raising the mitochondrial mass of HSCs. Therefore, more mitochondria are transferred to HSCs when a bacterial infection occurs [77].

MSCs-derived mitochondria, what makes them special

Mitochondria in MSCs usually present a perinuclear localization, but after differentiation mitochondria distribute more homogeneously throughout the cytoplasm [78, 79]. Furthermore, Bertolo et al. research on MSCs with higher expansion potential, showed that these cells exhibited an increased oxidative status determined by lower mitochondrial membrane potential, lower mitochondrial activity, lower levels of reactive oxidative species (ROS) production, and lower mitogenesis, compared to those with lower expansion potential [80]. Evidence has shown that ROS could modulate MSC fate, as high levels of ROS can impair osteogenic differentiation while promoting adipogenic differentiation [79, 81–84]. Interestingly, osteogenic and adipogenic differentiation have oxidative phosphorylation (OXPHOS) as a main source of ATP, and to a lesser extent chondrogenic differentiation [79, 85, 86]. In addition, Pattapa et al. observed a reduced oxygen consumption rate of MSCs differentiating into chondrogenic fate compared to osteogenic lineage, implying a higher contribution of glycolysis than ATP production [87]. Similarly, other cell processes can also lead to a metabolic switch in MSCs. Regarding migration, inhibition of ATP production by carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) treatment compromises cell migration [88]. In addition, the increase of intracellular ROS reduces immunosuppressive functions of MSCs, inducing mitochondria with lower membrane potential and mainly due to change from OXPHOS to favor a glycolytic state [89]. Interestingly, Guo et al. show that autologous mitochondria transfer to BM-MSCs exhibited significantly enhanced proliferation and migration, and increased osteogenesis upon osteogenic induction [90]. Together these findings show the importance of mitochondria over MSCs’ functions and properties.

According to the tissue from which MSCs were isolated and related to mitochondrial transfer capacity, AD-MSCs and BM-MSCs have shown a higher mitochondrial transfer to cardiomyocytes than DP-MSCs and WJ-MSCs [91]. Curiously, when these MSCs were analyzed by their oxygen consumption rates, mitochondrial respiration parameters (like ATP levels), basal and maximal respiration, and mtDNA copy number; DP-MSCs and WJ-MSCs showed higher parameters than AD-MSCs and BM-MSCs, resulting in a significant inverse correlation with their mitochondrial donation capacity. Notably, DP-MSCs and WJ-MSCs suppressed mitochondrial ROS levels in cardiomyocytes more effectively than AD-MSCs or BM-MSCs [91]. This background shows that the source from which MSCs are isolated affects the potential function of these cells.

Mitochondria are dynamic organelles, whose morphology, size and network can vary within cell type. As so, much cannot be said on the specific characteristics that mitochondria must meet to be transferred. However, the organelle’s small size, shape and dynamic nature allow it to be transported via different mechanisms. Even though mitochondria shape and size are highly variable, the multiple reshaping process should permit morphological variations suitable for transfer [34]. Mitochondrial membranes, characterized as dynamic and rich in cholesterol, similar to eukaryotic membranes, can also enhance the capacity of the organelle to be internalized by the receptor cell [34, 92]. Interestingly, different sources of mitochondria have different entry capacities than others. As shown by Court et al. fibroblast and PBMCs-derived mitochondria yielded lower mitochondrial transfer and failed to obtain a similar frequency of Treg compared to MSC-derived [72]. On the same note, mitochondria can also carry with them molecular signatures from the donor cells. When released by platelets, these organelles seem to display immune tolerance markers, such as CD270 and CD274 (PD-L1). When these mitochondria are internalized, they can modulate the proliferation and function of immune cells [93]. Interestingly, a subset of microRNA, named MitomiR, has been shown to play an important role in mitochondrial functions. Specific microRNA signatures are associated with specific type of cells and their status (differentiation, activation, polarization) as demonstrated recently by our group [94]. Nonetheless, much is still unknown regarding what makes mitochondria suitable for transfer, molecular cues and surface markers for export and internalization.

Mitochondria motivated by dynamic purposes

Mitochondria are organelles commonly located in the cytoplasm within cells, characterized by containing their DNA and being enclosed by a double membrane. In humans, mtDNA encodes 13 proteins, 22 tRNA and 2 ribosomal RNA genes necessary for their translation and maternally inheritance. All other proteins needed to maintain and express mtDNA are encoded in the nuclear DNA [95]. Structurally, the mitochondria are enclosed by the outer mitochondrial membrane (OMM), which is in contact with cytosol, while the inner mitochondrial membrane (IMM), folded into cristae, is in contact with the mitochondrial matrix, with an intermembrane space in between both [96]. These organelles are widely known for their ability to produce energy in the form of ATP, required by cells to function and survive, through the tricarboxylic acid (TCA) cycle and OXPHOS [97]. Nowadays, it is known that the mitochondria can also take part in many other biological processes including innate immunity [98, 99], apoptosis [100], calcium homeostasis [101] and more. Abnormal mitochondrial function and morphology have been linked to human-inherited disorders and common diseases, such as neurodegenerative disorders, cardiomyopathies, metabolic syndrome, cancer, and obesity [102].

Mitochondria are highly dynamic organelles, as they can modify their morphology by fusing and fissioning their membranes via the coordinated assembly of tubular networks [103]. Fusion refers to the union of two mitochondria resulting in one, contrary to fission that refers to the division of one mitochondrion into two daughter mitochondria. Mitochondrial fusion is a two-step process that involves GTPases mitofusins 1 and 2 (Mfn1 and Mfn2) and optic atrophy 1 proteins (OPA1) responsible for OMM and IMM fusion, respectively [104]. In comparison, mitochondrial fission is a three-step process composed of: (i) marking the fission site, (ii) ring-like structure formation with cytosolic dynamin-related protein 1 (DRP1) dimers and oligomers around the marked site and (iii) DRP1 constriction dependent of GTP hydrolysis [105]. As so, mitochondrial dynamics support the balance between these two coordinated processes determining the shape, size and location of the mitochondria within the cytoplasm [103, 104]. Mitochondrial function is ensured by transitions dynamically balanced that respond to cellular demands by adapting the mitochondrial network to metabolic cues and nutrient availability [106]. In fact, during energy production, by-products are generated exposing mitochondria to high levels of ROS, which can cause mtDNA mutations and can alter protein folding and structure [107].

Together with mitochondrial fusion and fission processes, mitochondria undergo biogenesis mitochondrial that produce new mitochondria and mitophagy that eliminate them [108, 109]. The correct equilibrium to generate more mitochondria according to bioenergetic needs and elimination of the dysfunctional mitochondria is the key to define the mitochondrial mass [108]. During mitochondrial biogenesis, which implies an increase in mitochondrial mass, the mitochondria genome and nuclear genome are involved in tightly coordinated processes to produce proteins involved in these processes [108]. Mitochondrial biogenesis is regulated by the peroxisome proliferator-activated receptor γ (PPARγ) and the PPAR-gamma coactivator (PGC) family, consisting of PGC-1α, PGC-1β and PRC, where PGC-1α is named the regulator master of mitochondrial biogenesis [110]. The PGC-1 family member potentiate a set of transcription factors to control the expression of proteins involved in mitochondrial biogenesis [111]. The PGC-1 family member expression is regulated by extracellular signals that control cell survival, death, or metabolism via post-translational modification by the AMP-activated protein kinase (AMPK) and the NAD-dependent deacetylase sirtuin-1 (SIRT1), favoring finally the newly synthetized mitochondria [111–113].

Conversely, the process to eliminate dysfunctional or damaged mitochondria through autophagy is called mitophagy. This process is essential to prevent the accumulation of poor-functional mitochondria and to regulate the mitochondria quantity according to energetic needs. In mitophagy, mitochondria are engulfed in autophagolysosomes and are degraded by lysosomes [114]. Mitophagy is mediated by the PINK1 (PTEN induced kinase 1)–Parkin pathway. In functional mitochondria, PINK1 is cleaved by proteases in the IMM. But in mitochondria with diminished membrane potential or accumulation of unfolded proteins, PINK1 is stabilized in the OMM where is activated by auto-phosphorylation, leading to Parkin recruitment and translocation to the mitochondrial surface [115, 116]. Thereafter, Parkin activation leads to the degradation of OMM proteins through proteasomal pathways and the specific autophagy of damaged mitochondria [115, 117, 118].

Metabolic changes: a trigger for mitochondrial dynamics

Further cell events that can trigger the activation of mitochondrial dynamic processes are metabolic changes. For instance, the change of mitochondrial respiration, or OXPHOS, to a glycolytic state, induces mitophagy to reduce mitochondrial mass [116]. In addition, MSCs physiologically reside in niches with low-oxygen tension or hypoxia, as the bone marrow [119]. MSCs in its undifferentiated state are characterized to maintain a glycolytic metabolic profile, where the main source of ATP necessary for the cell is obtained by glycolysis [84, 120, 121]. Interestingly, MSCs preconditioned in hypoxic conditions promote survival, proliferation, and angiogenic cytokine secretion, and result in a more efficient repair of segmental bone defect [122, 123]. In addition, the stimulation of the glycolytic program enhances the therapeutic potential of MSCs [124], via the enrichment of the Hypoxia Inducible Factor 1 Subunit Alpha (HIF-1α), which is highly expressed in stem cells and favors the maintenance of stem features regulating its metabolism and preservation of glycolytic state [121, 125]. In this context, MSC with a glycolytic metabolic profile are characterized by low mitochondrial content [84], low O₂ consumption rate [84, 121], an increase of lactate production that characterizes the glycolytic flux [84, 87, 125], relative low ATP levels [84, 121, 125], and elevated glycolytic enzymes when compared with more differentiated cells [84, 126, 127].

As mentioned before, a cell can switch between metabolic states, a phenomenon seen in MSCs upon differentiation [84, 121]. MSCs are characterized by their ability to differentiate into osteoblasts, adipocytes and chondrocytes. MSCs’ differentiation is a high-energy demanding process, which is one of the reasons MSCs suffer a metabolic shift towards OXPHOS, to meet higher energy requirements [84, 86]. Interestingly, Hofmann et al. observed that during adipogenic differentiation, the enzyme complexes involved in OXPHOS were organized in supramolecular complexes, thought to boost electron transport chain efficiency [78]. Researches also have found that during differentiation, there is an increase in biogenesis mitochondrial [78, 84, 86]. Morphology and distribution of mitochondria are also altered upon differentiation, becoming more elongated and connecting to form a network [121]. The processes of mitochondrial dynamics: fusion–fission [104–106], genesis [106, 108, 110–112], and degradation [107, 116, 118, 128] respond to the metabolic state and requirements of cells and can be regulated by intrinsic and extrinsic mechanisms. Thus, the number, morphology and half-life of this organelle must be tightly regulated, not only for endogenous or own mitochondria, but also upon an event of mitochondrial transfer from one cell to another [105, 108, 112, 129].

Internalization of exogenous mitochondria

Transferred mitochondria, when internalized by the receptor cell, can undergo distinct fates and greatly modify cellular functions, which will depend greatly on the fate of the transferred mitochondria inside the cell [24, 25, 130, 131]. For instance, mitochondria from MSCs transferred to neural stem cells (NSC), are apparently not degraded, as mitochondria integrate to NSC mitochondrial network, increase the mitochondria membrane potential and favor the NSC survival [132]. Otherwise, Chung-ha Davis et al. observed that retinal ganglion cell axons not only are capable of shedding mitochondria at the optic nerve head, but also the shedded mitochondria are internalized by astrocytes in the surrounding areas and degraded, in a process known as: transcellular degradation of mitochondria, or transmitophagy [129]. This process has not only been described in neuronal cells [129], but also in MSCs [73]. MSCs can transferred their depolarized mitochondria in vesicles to macrophages. These macrophages engulf and reuse these vesicles containing mitochondria resulting in an improved bioenergetics [73].

On the other hand, techniques such as fluorescent and electron microscopy, mitochondrial isolation and artificial transfer, have allowed to properly study the fate of the exogenous mitochondria. Confocal microscopy of two-colored labeled mitochondria in a coculture systems of fibroblasts and epithelial cells has shown the integration of the exogenous organelle into the endogenous network [133]. Furthermore, other key parameters such as oxygen consumption, mitochondrial mass, volume and copy number increase upon mitochondrial transfer [133–135].

Three-dimensional super-resolution structure microscopy and electron microscopy have revealed that isolated mitochondria are internalized by human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) and human cardiac fibroblasts (HCFs) through the endolysosomal system, from which most escape and integrate to the endogenous network [136]. In agreement with this result, immunoblot experiments for major mitochondrial dynamics proteins showed an increased expression of mitochondrial fusion molecules [136]. In addition, Levoux et al. show that once MSCs endocyte mitochondria from platelets, their mitochondrial network exhibit many fused mitochondria [137]. These current findings support the notion of exogenous mitochondrial integration.

Mitochondria responding the emergency call

Cell-to-cell communication is an important physiological process that promotes the maintenance and development of multicellular organisms, tissue homeostasis and disease progression, through the interaction of constituting cells with target cells in close proximity or further away. These types of interactions are mediated by different means, such as vesicles or direct passage via cellular structures, such as gap junctions (GJs), actin structures and plasmodesmata. The cargo that is capable of moving from one cell to another can range from molecules to organelles [68, 138]. Multiple reports of intercellular organelle movement between like and different cell types have shown to increase the cell’s energetic profile, reduced autophagy and ROS production, and improve disease phenotype [68, 138, 139].

One remarkable finding concerning these actions has been the description of mitochondrial exchange from donor cells to damaged tissues, in response to target cell stress. So far, several groups have reported the horizontal transfer of mitochondria in multiple cell lines, both in vitro and in vivo. Remarkably, mitochondrial transfer can take place in physiological conditions. In fact, the exchange of mitochondria plays a pivotal role in cellular and tissue homeostasis, as well as tissue development. As shown by Sinclair et al., lung tissue MSCs (LT-MSCs), harvested from health lung sections, transfer mitochondria to non-tumorigenic epithelial cell line [140]. Furthermore, mitochondrial transfer has also been recorded between MSC and rat renal tubular cells in coculture, allowing the induction of MSCs differentiation into kidney tubular cells [141]. On the other hand, most of the evidence surrounding mitochondrial exchange and delivery between cells comes to terms with the rescue of pathological conditions or damaged tissues and cells. MSC-induced mitochondrial exchange was first assessed in a model of LPS-induced lung injury, in which the intra-tracheal administration of MSCs to LPS-treated mice was associated with the transfer of mitochondria to alveolar epithelium [24]. MSCs triggered an increase in the concentration of ATP, metabolic activity and also an improvement in lung damage while reducing mortality in the diseased animals [24]. In vitro mitochondrial exchange has tested the possibility of mitochondrial movement between effective donor cells, such as MSCs, to a broad range of receptor cells. Spees et al. reported the transfer of healthy mitochondria to ethidium-bromide mtDNA-depleted recipient cells, which were not able to survive in standard media. Respectively, cells devoided from intrinsic mitochondrial function were coculture with stem cells, acquiring functional mitochondria and reestablishing their aerobic function [35, 142]. Thus, suggesting that in mitochondrial transfer the use of healthy, exogenous sources of mitochondria into damaged tissues can result in the rescue of cells or tissues from various types of damage.

Regarding the possibility of mtDNA being released, it is well reported that mtDNA triggers inflammatory response due to recognition, known as Damage-Associated Molecular Patterns (DAMPs). MtDNA can be detected by TLR (Toll-like receptor), a receptor expressed on immune cells. This recognition triggering the activation of several inflammatory pathways as activation of pro-inflammatory nuclear factor kappa B (NF-κB), nucleotide-binding domain, and leucine-rich repeat (NLR) prying domain-containing 3 (NLRP3) inflammasomes, and interferon regulatory factor-dependent type 1 IFN [143]. In addition, mtDNA can be part of Neutrophil Extracellular Traps (NETs), a structure secreted by neutrophils that traps DNA, bacteria, and proteins, among others, that favor the propagation of inflammation [143, 144]. However, in MSCs, it is reported that during mitochondrial transfer to macrophages, MSCs also secrete microRNAs containing exosomes that interfere in the TLR activation, favoring that inflammatory response does not occur [73]. This antecedent demonstrates how MSCs avoid inducing or incrementing inflammation to maintain their immunoregulatory properties.

Mitochondria transfer within the niche

Mechanisms of transfer that do not rely on long-distance or secreted structures have also been reported in the literature (Fig. 3). For instance, cell fusion, where two cells transitorily or completely fuse their membranes and share cytosolic compounds, such as organelles, while the nucleus remains intact. This phenomenon has been reported in myeloid and lymphoid cell progenitors, which fuse in low rates as a response to injury or inflammation [142, 145, 146]. Oh et al. reported cell fusion on a model of myocardial infarction after stem cell therapy between cardiomyocytes and bone marrow-transplanted cells [147]. Other mechanisms of transfer use the aid of structures known as GJs. In fact, MSCs can attach to cells for molecule and organelle exchange in regions of high connexin expression, compact architecture, short membrane nanotubes and direct cell–cell connections involving lose junctions, such as hemi-connexins and cytoskeletal structures [139]. Indeed, BM-MSCs formed Connexin43-mediated gap junctional channels with the alveolar epithelium, which allowed the transfer of mitochondria that led to cellular protection upon infection [24, 139, 142]. Interestingly, MSCs not only transfer mitochondria, but also can accept mitochondria from cells in their niche, such as HSCs. Golan et al. showed that upon injury, such as irradiation, MSCs suffered mitochondrial damage that promoted organelle transfer via connexins, improving cellular bioenergetics. It was this improvement in mitochondrial dysfunction that allowed for a better engraftment of transplanted HSCs [148]. On the same note, Dong and colleagues injected mouse melanoma cells devoid of mtDNA (B16ρ⁰) into syngeneic mice that express a red fluorescent protein in their mitochondria. Results showed that B16ρ⁰ cells acquired whole mitochondria. This mitochondrial transfer within the tumorigenic niche led to a rapid recovery of respiratory function and efficient tumor-forming capacity [149]. Together these findings support the notion and role of mitochondrial transfer within different niches.

Mitochondria computing the tunneling nanotubes network

Even though the mitochondrial exchange has been well reported in the literature, the mechanisms and signaling pathways that underlie the transfer process remain unclear. Upon injury, damage or stress, the cell likely possesses mechanisms to trigger organelle exchange to recipient cells emanating these signals. The formation of channels and membrane-like structures that allow the transfer of mitochondria have been visualized and described as tunneling nanotubes (TNTs) (Fig. 3). As described by Rustom et al., TNTs are long-distance tubular structures or projections that have a diameter between 50 and 150 nm and are able to connect different cells together [31]. TNTs do not attach to the substrate of the cell nor are tethered to the extracellular matrix. However, they rely on cytoskeleton fibers of actin and microtubular origin, to provide a continuity of the plasma membrane and the cytoplasm of two different cells, acting as trafficking route of different cellular components [31, 138]. Release and donation of mitochondria is a highly orchestrated process, in which much remains unclear. As such, the formation of TNTs and mitochondrial motility inside these structures are a well-regulated process by proteins known as TNFAIP2 and Miro1 along with accessory proteins, such as Miro2, TRAK1, KHC and Myo19. The latter proteins allow mitochondria to attach to microtubules [71, 150–152]. While TNFAIP2 and Miro1 allow the formation of the nanotubule and the efficient delivery of mitochondria to recipient cells. Knockdown of TNFAIP2 decreases the number and stability of TNTs. Inhibition of Miro1 does not prevent the formation of TNTs but retards mitochondrial movement. Contrary, the overexpression of Miro1 in MSCs was responsible for an enhanced mitochondrial transfer and therapeutical effect in an epithelial injury model, while Miro1 knockdown leads to loss of efficacy [71]. This method appears to be essential for transferring mitochondria in some cell types, as chemical impairment of the structures significantly reduces mitochondrial exchange [138, 142]. These data show that mitochondrial donation is a well-directed process, and not only a stochastic exchange of cellular contents [71, 150–153].

Alternative routes for mitochondria transfer

Another mechanism by which MSCs exert their therapeutic effects on recipient cells is via EVs and apoptotic bodies, which are a group of heterogeneous vesicles, ranging from 400 to 1000 nm, that are secreted by different types of cells to the extracellular medium [142]. EVs are formed by three different groups of vesicles, classified depending on varying sizes, origin and composition. Larger EVs, such as microvesicles (MVs) and apoptotic bodies, can be loaded with partial or entire mitochondrial particles and mitochondrial genome. While smaller EVs, such as exosomes, can only contain genetic material, including mtDNA [142, 154]. For instance, in an in vitro model for stroke, astrocytes generated MVs, which were large enough to contain whole mitochondria with respiratory function that when injected into mice with ischemic brain damage, vesicles associate with damaged neurons improving mice survivability [154]. The release of astrocytic mitochondrial particles was regulated by a calcium-dependent mechanism involving cyclic ADP ribose and CD38 signaling, as suppression of CD38 by siRNA reduced mitochondria transfer and diminished functional outcomes [154, 155]. While Phinney et al. studied the effects of MSCs on the intracellular stress response, showing that MSCs prompt the movement of depolarized mitochondria into the outer limits of the plasma membrane as a response to a higher concentration of oxygen, in EVs larger than 100 nm. These EVs were loaded with mitochondria and secreted via arrestin domain-containing protein 1, and can fuse with macrophages, enhancing their oxygen consumption rate [73, 142, 146]. Interestingly, to avoid adverse reactions on macrophages, from mitochondria engulfment, MSCs also released microRNA-containing exosomes that de-sensitize macrophages via TLR signaling suppression [73]. Although there is building evidence that shows the signaling pathways sensitive to MVs mitochondrial transfer, the exact molecular regulation is still unknown.

More recently, several groups have described the presence of functional mitochondria in large vesicles, as a mechanism of mitochondrial intracellular transfer. In addition, Ikeda et al. showed that vesicles obtained from human induced pluripotent stem cell-derived cardiomyocytes (iCMs) media were enriched in functional mitochondria that were not only able to integrate into the endogenous mitochondrial network, but also have an effect on ATP production in vitro and improved contractile properties of iCMs in an in vivo model for murine myocardial infarction [156]. Further evidence of mitochondrial transfer via vesicle trafficking has also shown functional effects on neuronal cells treated with rotenone or carbonyl cyanide 3-chlorophenylhydrazone (CCCP) to damage the endogenous mitochondria. Synaptosomes containing functional mitochondria restores mitochondrial membrane potential after rotenone or CCCP treatment [157]. Taken together these results suggest that functional and respiring mitochondria can be shuttle inside vesicles and improve intracellular energetics in different receptor cells.

Mitochondria in vesicles: a safer way to travel?

Even though most evidence and literature deal with mitochondrial exchange through cellular mechanisms, there is an ongoing body of evidence that demonstrates that mitochondria could be released to the extracellular medium. This observation has been published previously mainly related to inflammatory or licensing conditions [74, 75, 158]. Boudreau et al. showed that activated platelets release mitochondria in two ways, naked and as membrane-rounded microparticles [75]. The authors showed that mitochondria release promotes inflammation when being recognized by secreted phospholipase A2 IIA (sPLA2-IIA), a phospholipase normally specific for bacteria. Interestingly, mitochondria themselves can secrete vesicles. Todkar et al. working with RAW264.7, a macrophage cell line, showed that mitochondria-derived vesicles did not have pro-inflammatory properties because mitochondria regulated the packaging of mitochondrial proteins in EVs, demonstrating how mitochondria can control vesicle content release to not generate inflammation [159].

The discovery of mitochondria in the extracellular medium was correlated to diseases characterized by microparticles released from platelets in osteoarthritis and rheumatoid arthritis. In fact, membrane-rounded naked mitochondria microparticles were found in synovial fluid samples of patients evaluated by transmission electron microscopy [75]. The secretion of membrane-rounded mitochondria by platelets was corroborated by Levoux et al. findings through the visualization by transmission electron microscopy; they demonstrated that released mitochondria from platelets are transferred to MSCs to improve the capability to favor wound healing [160]. In agreement with mitochondria released and its contribution to inflammation, Puhm et al. showed that LPS-stimulated monocytes released naked mitochondria and mitochondria embedded in MVs with pro-inflammatory potential. These naked mitochondria and MVs induce Type I interferon (IFN) and tumor necrosis factor (TNF) signaling pathways in human umbilical vein endothelial cells (HUVECs). Interestingly, pro-inflammatory features of mitochondria are correlated with the inflammatory state of cell of origin [74]. Extracellular mitochondria have also been found in cerebrospinal fluid (CSF) of rats and humans after subarachnoid hemorrhage (SAH). Even though the authors did not examine the role of these mitochondria in disease, they found a correlation of higher mitochondrial membrane potentials in CSF with suitable clinical recovery after SAH onset [161]. On the other hand, Mobarrez et al. showed an increase of microparticles released in plasma of systemic lupus erythematosus patients, where they also found microparticles containing mitochondria evaluated by the expression of translocase outer mitochondrial membrane 20 (TOM20) and Hexokinase 1, and the mitotracker dye [158]. Despite that, there is a correlation between microparticles containing mitochondria with the disease activity, and the authors did not study the functionality of these mitochondria in patients. However, concluded that mitochondria can form part of immune complexes, as a conglomerate of antigens and antibodies that mediate the morbidity of the disease [158].

Currently, the presence of cell-free respiratory mitochondria circulating in blood was demonstrated by Dache et al., where the authors showed the presence of extracellular mitochondria in the plasma of healthy donors [162]. Mitochondrial respiration was assessed by oxygen consumption rate, and despite showing a low-oxygen consumption rate compared to intracellular mitochondrial evaluation, it has remarkable considerations, as samples were taken from healthy donors, and opens the possibility to find free mitochondria in humans’ blood [162]. Dache et al. findings are corroborated with Stephens et al. studies that show extracellular circulating mitochondria in healthy murine and human blood with modulable membrane potential [163]. On a similar note, Song et al. demonstrated that circulating mitochondria from blood can modulate CD4+ and CD8+ T cells. Even though mitochondria induced more activated T cells, these produced less inflammatory cytokines as IFN-γ and interleukin-12 (IL-12), demonstrating the regulatory capacity of mitochondria on immune cells that could favor homeostasis maintenance [164].

Thus, mitochondria can be released in healthy, disease or inflammatory conditions or to regulate the metabolic status of the cells. These mitochondria could have regulatory or inflammatory effects depending on the cell of origin and the microenvironment they are released. However, the tight correlation of mitochondrial cellular origin and the cell state remains to be examined to elucidate the mitochondria’s potential effects once released on its targets. In this context, vesicles containing mitochondria released by MSCs is a mechanism described to mitochondrial transfer [142]; however, the release of naked mitochondria by MSCs have not been reported nor studies that compare the effect or differences between naked mitochondria and mitochondria embedded in vesicles. It is possible that mitochondria embedded in vesicles are a safer way to release them because the mitochondria could be more protected from the external insult, opening the possibility to longdistance mitochondrial transfer. On this same note, Ikeda et al. show that EVs containing mitochondria isolated from the supernatant of iCMs restored the mitochondrial function, contractile property and cell survival of hypoxia-injured iCMs, in contrast, mitochondria isolated by iCMs did not obtain these results [156]. This work shows that vesicles are an efficient mitochondria transport way. On the other hand, Boukelmoune et al. propose that MSCs can transfer mitochondria to neural stem cells (NSC) to protect against neurotoxic effects of cisplatin treatment [132]. With the results of this research, it is possible to suggest that MSCs away from NSC could release mitochondria in EVs to mediate the protective effect on NSC.

Even though an investigation is required to clarify the molecular mechanisms associated with the destiny and integrity of these vesicles loaded with mitochondria, MSCs’ transplant can act as a sure vehicle to transport mitochondria. When transplanting cells, the need arises for all cellular mechanisms that trigger mitochondrial transfer; this could be a disadvantage. In addition, in some contexts, the size of MSCs could be a disadvantage in organs with difficult access like the brain. On the other hand, the transplant of isolated mitochondria has the disadvantage that could be not sufficiently protected of extracellular medium, overall the concentration of extracellular calcium [165]. Despite this, considering that mitochondria may be contained in vesicles, this can be a useful protection to the insult of the extracellular medium. The advantages of transplanting mitochondria directly can favor entry to sites with difficult access due to their small size. Despite the risk of the extracellular medium that can affect isolated mitochondria, it is used in acute limb ischemia (ALI) murine model where mitochondria were delivered to each muscle resulting that mitochondria improve skeletal muscle injury and enhancing hindlimb function [166]. Remarkably, the transplant of autologous mitochondria harvested from nonischemic skeletal muscle has been used in pediatric patients with ischemia–reperfusion injury, the result of the treatment show an improvement in the ventricular function [28], demonstrating that transplantation of isolated mitochondria results in a sure and effective treatment.

Mitochondria transfer, a novel mechanism of action behind MSCs’ therapies

During the past decade, many studies demonstrating the therapeutical and clinical effects of mitochondrial transfer have surfaced. Mitochondrial exchange is currently being considered as one emerging mechanism of action through which MSCs can be beneficial for multiple cellular processes, such as wound healing to regenerate and repair damaged cells or tissues. Different preferred mechanisms and modes have been observed based on concerned recipient cells and stress conditions (Fig. 4). Remarkable restoration of cellular bioenergetics and reduction in oxidative stress has been achieved in studies that demonstrate that mitochondria transfer from MSCs plays a critical role in cellular repair and regeneration (Table 1). It has been evident that this transfer is a major key in immune regulation, healing several diseases related to brain injury, cardiac myopathies, muscle sepsis, lung disorders and acute respiratory disorders.

Fig. 4 — Tissue-specific MSCs’ mitochondrial transfer and its mechanism to receptor cells of different origins in various pathophysiological conditions, such as: *Mitochondrial transfer in lung injury*, such as acute lung injury, asthma, chronic obstructive pulmonary disease, and rotenone-induced lung injury. MSCs-derived mitochondrial transfer to pulmonary alveoli and lung epithelia contributed to protection from acute lung injury, mitochondrial bioenergetics, and ATP production, while reducing cytokine production, programmed cell death, and animal mortality [24, 71, 167, 168]. *Mitochondrial transfer in stroke models* can alleviate the pathological symptoms of stroke, provoke a restoration of neurological activity, reduce brain lesion volume, inflammatory response, apoptosis, and restore the bioenergetics of the recipient cells and stimulate their proliferation [177–179]. *Mitochondrial transfer in heart injury* has shown to restore damaged cells’ functions, prevent cell death, increase the mitochondria potential, and rescue aerobic respiration and cells from apoptosis [26, 172–175]. *Mitochondrial transfer in other tissues* have demonstrated to have the ability to combat infection by enhancing macrophage bacterial phagocytosis in the harmed tissue [18, 25]. Furthermore, mitochondrial ATP generation appeared to control the insulin secretion from islet β-cells in response to high extracellular glucose level, improving function of insulin cells and other cells in the diabetic niche [169], while mitochondrial transfer in HSCs and the bone marrow niche have been used and tested in Pearson Syndrome (PS) and Kearns–Sayre syndrome (KSS). To improve HSCs’ function, aerobic capacity and mitochondrial membrane potential [62, 63]

Table 1.

Therapeutical applications of transplantation of MSCs-derived mitochondria and non-MSCs-derived mitochondria in various conditions

	Source	Target cells	Target disease	Effects	References
Coculture	iPSC-MSCs	Epithelial cells	Asthma inflammation	Alleviates asthma inflammation Decreases T helper 2 cytokine Decreases mitochondrial dysfunction of epithelial cells	[208]
	BM-MMSCs	Somatic cells with non-functional mitochondria	Tissue repair	Decreases production of extracellular lactate Decreases level of ROS Increases intracellular ATP Increases membrane potential Increases oxygen consumption	[35]
	UC-MSCs	T cells	Immune disease	Regulates autophagy Inhibits respiratory mitochondrial biogenesis Decreases T cell apoptosis	[72]
	iPSC-MSCs	Airway epithelial cells	Obstructive pulmonary disease	Rejuvenates damaged lung cells Increases alveolar surfactant Increases intracellular ATP	[24]
	hMMSCs	Renal tubular cells	Acute renal failure	Restores renal function status Increases intracellular ATP Increases oxygen consumption	[170, 209]
	BMSCs	Alveolar macrophage, alveolar epithelium	Acute respiratory distress syndrome	Increases alveolar macrophage phagocytosis Increases antimicrobial mechanism Decreases production of inflammatory factor Increases production of ATP Decreases severity of alveolar destruction and fibrosis	[18, 25]
	iPSC-MSCs BM-MSCs	Cigarette smoke-exposed airway epithelial cells	Chronic obstructive pulmonary disease	Decreases alveolar destruction Increases intracellular ATP	[167]
	iPSC-MSCs BM-MSCs	Cardiomyocytes Cardiomyoblasts	Ischemia/reperfusion Vascular disease	Prevents late cell death Increases mitochondria potential Increases gene expression in early cardiac commitment through partial cell fusion Recovers aerobic respiration Increases resistance against the ischemia/reperfusion apoptotic system Rescues aerobic respiration Protection from apoptosis Increases mitochondrial membrane potential	[172, 174, 175]
	hMMSCs	Astrocyte	Ischemia	Restores bioenergetics profile of recipient cells Stimulates proliferation	[178]
	hMMSCs	Cortical neurons	Stroke	Mitigates the pathological symptoms Restauration of neurological activity Reduction of brain lesion volume Alleviates inflammatory response Reduces apoptosis Rescues injured cells	[177]
	MSCs	Islets β-cells	Diabetes	Improves islet secretory functions Increases intracellular ATP	[169]
	hMMSCs	Renal proximal tubular epithelial cells	Diabetic nephropathy/diabetes	Suppresses apoptosis of damaged cells Inhibits ROS production Enhances the expression of mitochondrial superoxide dismutase 2 and Bcl-2 expression	[170]
	hMMSCs	Rat renal tubular cells	Diabetic nephropathy	Promotes differentiation into kidney tubular cells	[141]
	MSC/ECs	Cancer cells	Cancer	Promotes chemoresistance Decrease ROS production Contributes to proliferation and migration of cancer cells Increases intracellular ATP Favors the synthesis of metabolic intermediates to support the production of new biomass/cancer cells	[184, 189, 190, 193]
	iPSC-MSCs	Corneal damage and vision impairment	Corneal epithelial cells	Wound healing Protection against oxidative-stress-induced mitochondrial damage Protection against cell death and proliferation-inhibition	[180]
Injected mitochondria	Non-MSCs-derived mitochondria*	Nonischemic region mitigated myocardial injury	Liver ischemia/reperfusion injury	Significantly reduces I/R injury in the liver Supplements a working ROS scavenging system Increases ATP	[210]
		Tissue unaffected/myocardium	Ischemia/reperfusion Cold ischemia time (CIT)	Enhances myocardial function and cell viability Enhances post-ischemic functional recovery Decreases liver tissue injury and apoptosis Enhances graft function and Decreases graft tissue injury Increases in coronary blood flow	[211, 212]
		Human osteosarcoma cybrids	Parkinson’s disease	Increases mitochondrial function resulting in a resistance to neurotoxin-induced oxidative stress and apoptotic death Increases capacity for neurite outgrowth Improves locomotive activity in rats Decreases dopaminergic neuron loss	[213]
		Parent cybrid cells	Mitochondrial DNA mutation (myoclonic epilepsy with ragged-red fibers (MERRF) syndrome)	Mitochondrial function recovery and cell survival by preventing mitochondria-dependent cell death Increases mitochondrial biogenesis	[214]
		Nonischemic skeletal muscle	Dysfunction after ischemia–reperfusion injury Acute limb ischemia	Restores mitochondrial function and viability Improves post-ischemic myocardial function Ameliorates skeletal muscle injury Enhances hindlimb function in the murine model	[166]
		Brain macrophages, endothelium, pericytes, glia	Spinal cord injury: L1/L2 contusion	Microinjection into the spinal cord significantly restores respiration No differences in locomotion or kinematic stepping patterns	[215]
		Multiple tissues	Non-alcoholic fatty liver disease	Intravenously injected of mitochondria decreases serum aminotransferase activity and cholesterol level in a dose-dependent manner Reduces lipid accumulation and oxidation injury of the fatty liver mice Improves energy production Restores hepatocyte function	[216]
		Multiple tissues	Acetaminophen-induced liver injury	Intravenously injection of mitochondria increases hepatocyte energy supply Reduces oxidation stress Ameliorates tissue injury	[217]
		Renal tubular epithelium of the cortex and medulla	Acute kidney injury	Intra-arterial injection of mitochondria increases glomerular filtration rate and urine output Decreases serum creatinine and blood urea nitrogen Transplanted kidney shows patchy mild acute tubular injury	[218]
		Peri-infarct cortex	Transient focal cerebral ischemia	Upregulation of cell-survival-related signals in MCAO mice	[154]
	MSCs-derived mitochondria	Macrophages	ARDS	Lung macrophages that acquire MSC mitochondria increase phagocytic activity and anti-inflammatory phenotype	[18, 25]
		Alveolar epithelia	Acute lung injury	Intranasal instillation of mBMSCs increased alveolar ATP Abrogates alveolar leukocytosis and protein leak inhibits surfactant secretion Decreases high mortality	[24]
		Macrophages and several brain regions	Chemotherapy-induced cognitive deficits	Two nasal administrations of mitochondria restored the impaired working and spatial memory chemotherapy-induced	[219]

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*The non-MSCs-derived mitochondria were isolated from different cell types, and the benefits effects of the therapy were annotated

Lung diseases and tissue repair

Plenty of studies looked into the lung diseases’ model. One of the primary important studies was the work carried out by Islam et al. that demonstrated that BM-MSCs transfer mitochondria to pulmonary alveoli that could contribute to protection from acute lung injury. In their work, they highlighted that BM-MSCs could be used to supply healthy mitochondria to alveolar epithelial cells in a mouse model of E. coli LPS-induced acute lung injury [24]. It was reported that the transfer promoted the repair of mitochondrial bioenergetics with a significant increase of ATP concentration level in the recipient cells leading to the recovery of epithelium functions in the lung. Epithelial mitochondrial dysfunction is critical in asthma pathogenesis, Ahmad et al. notably observed the transfer of mitochondria through TNTs’ structures between mesenchymal and damaged epithelial cells which then have a protective effect on the recipient cells. This study was performed in a rotenone-induced lung injury mouse model and further confirmed in allergen-induced asthma models [71]. Furthermore, Li X et al. on their part studied and exhibited the effects of mitochondrial transfer in rat models exposed to cigarette smoke for 56 days that induced lung damage and the manifestation of chronic obstructive pulmonary disease. They noted that the effect was decreased as a result of the transfer of mitochondria through TNTs between BM-MSCs to lung epithelium [167]. MSCs mitochondrial transfer has also been shown to play an important role in cecal-ligation and puncture-induced sepsis, as exposure of lung epithelial and endothelial cells to mitochondrial-rich fractions, restored oxygen consumption rate and reduced total ROS production. Rat survivability was also improved in terms of lung mechanics and keratinocyte growth factor expression and survival rate; while reducing peritoneal bacterial load, inflammatory cytokines production and programmed cell death [168]. Thus, revealing a pivotal role of mitochondria in tissue repair.

Improving macrophage response

MSCs have been demonstrated to have the ability to combat infection by transferring mitochondria through tunneling nanotube-like structures to macrophages to enhance the immune response. It was reported an increase in intracellular ATP activity. This transfer enhanced macrophage bacterial phagocytosis in the harmed tissue, provoking the improvement of the process of repair [25]. In this study, Jackson et al. showed evidence that the transfer between MSCs and macrophages could play an important role in the immune response in preclinical models of ARDS, as direct coculture of MSC with monocyte-derived macrophage increased the OXPHOS of the recipient macrophages and then stimulates their phagocytic activity. These results were also validated in vivo, when E. coli-infected mice treated with intranasal Clodronate Liposomes (CL) to completely abrogates alveolar macrophages showed no MSC antimicrobial activity, suggesting alveolar macrophages as cell mediators of MSCs effect in this mice model [25]. Furthermore, the group of Morrison also evidenced that upon coculture of MSCs, human monocyte-derived macrophages augmented their phagocytic capacity and M2 markers [18]. These data suggest that mitochondria transfer from MSC to innate immune cells induces the enhancement of phagocytic activity and reveals an important novel mechanism for the antimicrobial effect of MSC in ARDS.

Regulating insulin release

As well, Rackham et al. published their work where they studied whether improvement of islet function is associated with mitochondrial transfer from MSCs to cocultured islets. In type 1 diabetes (T1D) condition, allogenic islet transplantation is possible for a small subgroup of people with one major obstacle, the limited availability of human islet material. This transplantation requires a short period to make the safety tests, administration of the transplants recipient to hospital and induction immunotherapy [169]. This period is critical and the functional viability of islets is compromised by inflammatory, oxidative and hypoxic stresses. At this list of negative factors, cold ischemia time and oxygen supply are added during pancreas procurement that also induce islet cell loss. Mitochondrial ATP generation appeared to control the insulin secretion from islet β-cells in response to high extracellular glucose levels. They showed in their work the mitochondrial transfer from human adipose MSCs to human islet β-cells in coculture through tunneling nanotube-like structures and microvesicles to hypoxia-exposed mouse islets to support the secretory function of compromised β-cells [169]. Interestingly, mitochondrial transfer not only improves the function of insulin cells, but also other cells in the diabetic niche. For instance, in diabetic nephropathy, in vitro BM-MSCs-derived mitochondrial transfer to renal proximal tubular epithelial cells reduces apoptosis and ROS production, as it enhances the expression of the enzyme mitochondrial superoxide dismutase 2 that binds to superoxide by-products and the apoptosis-related molecule Bcl-2. Furthermore, mitochondrial transfer also inhibited the translocation to the nucleus of mitochondria biogenesis factor PGC-1α, while local injection of BM-MSCs-derived mitochondria into streptozotocin (STZ)-induced diabetic rats ameliorates proximal tubular epithelial cells’ morphology and structure, suggesting a therapeutical effect of MSCs-derived mitochondrial transfer for diabetic-related conditions [170].

Saving cardiac tissue

As the heart is the organ with high-energy requirement, mitochondria occupy a large portion of cardiomyocytes, and are located between the myofibrils and just below the sarcolemma [171]. Mitochondrial transfer from MSCs to cardiac cells has been described using cell fusion and reprogramming of progenitor cells. Attila Cselenyak et al. revealed the beneficial effects of the MSCs coculture in an in vitro ischemia model, which seem to be dependent on direct cell-to-cell connections and intercellular nanotubes [172]. They found that the nanotube formation could take place frequently between cardiomyoblasts and mesenchymal stem cells. The mitochondrial transfer restored the damaged cells’ functions, prevented later cell death and increased the mitochondria potential in the later cells [172]. Furthermore, the MSCs were reported to have the capacity to reprogram fully differentiated mouse cardiomyocytes back to a cardiac progenitor-like state which occurs by mitochondrial transfer from MSCs with increased gene expression in early cardiac commitment through partial cell fusion [26]. Kaiming Liu et al. also described the transfer of mitochondria but this time between MSCs and human umbilical vein endothelial cells through tunneling nanotube-like structure [173]. They noted that inducing an oxygen glucose deprivation and re-oxygenation on human umbilical vein endothelial cells induced the mitochondrial transfer to injured vascular endothelial cells. This rescue mechanism was detailed to rescue aerobic respiration and protection of endothelial cells from apoptosis [173]. Later, Hui Han et al. investigated the mechanism of mitochondrial transfer between BM-MSCs to H9c2 cardiomyocytes. They reported that H9c2 cardiomyocytes increased apoptotic indexes, resulting from ischemia/reperfusion (SI/R) injury, and were significantly reduced after coculture with BM-MSCs [174]. This marked resistance against the SI/R-induced apoptotic process was achieved through mitochondrial transfer via TNTs [174]. A study by Yueling Zhang et al. demonstrated that human induced pluripotent stem cell-derived MSCs (iPSC-MSC) were more able to transfer their mitochondria compared with BM-MSCs due to the high expression of intrinsic Miro1 to rescue HUVECs with dysfunctional mitochondria [175]. In this study, they highlighted the formation of TNTs that is regulated via the TNF-a/NF-kB/TNFaIP2 signaling pathway. The rescued cells were noted to effectively attenuate anthracycline-induced cardiomyocyte damage, also, aerobic respiration was recovered, and apoptosis of ischemic endothelial cells (ECs) was reduced as a consequence of the mitochondrial transfer [175].

Neuronal protection

Mitochondrial transfer has appeared as a great therapeutic strategy as it can restore the bioenergetic level of damaged cells. Recent evidence has shown that cells in the nervous system can physiologically release and uptake mitochondria from neighboring cells [154, 176]. In fact, astrocytes can release functional mitochondria in EVs, which are received and internalized by neurons. This exchange of the organelle is facilitated by CD38/cyclic ADP ribose, a calcium-depending mechanism, and amplifies cell survival signaling after a transient focal cerebral ischemia in mice. Interestingly, suppression of CD38 not only deteriorates neurological outcomes, but also decreases the release of mitochondria in EVs [154]. A study by Babenko et al. observed in coculture an in vitro system transfer of mitochondrial between MSCs to rat cortical neurons to alleviate the negative impact of stroke [177]. They reported that injection of MSCs post-ischemia could mitigate the pathological symptoms of stroke and provoke a restoration of neurological activity. The transfer of mitochondria from the MSCs to the recipient neurons induced as effects a reduction of brain lesion volume, alleviates the inflammatory response, reduces apoptosis, and eventually rescues the injured cells. The level of Miro1 was increased in multipotent MSCs (MMSCs) after cocultivation. They concluded that the exchange by cellular compartments between neural and stem cells improves MSCs’ protective abilities for better rehabilitation after stroke [177]. The following study from Babenko et al. in 2018 shows that under oxidative stress, the transfer of mitochondria between MMSCs to neural cells can occur [178]. They found an exchange of mitochondria from MMSCs to astrocytes when the cells were exposed to ischemic damage associated with elevated ROS levels. This exchange restored the bioenergetics of the recipient cells and stimulated their proliferation. In this study, Miro1 seemed to be a key player in this transfer, enhancing the mitochondrial transfer [178].

Alexander et al. have shown that two nasal administrations of mitochondria isolated from human MSCs to mice restored the impaired working and spatial memory [179]. These findings indicate that the mitochondria from MSC can enter brain meninges and parenchyma and can be internalized by macrophages and various brain regions, including the hippocampus. In addition, they demonstrated that this mitochondrial administration induces changes in the hippocampal transcriptome, and the top canonical pathway identified is the Nrf2-mediated response [179]. This research shows an interesting strategy for reversing the cognitive deficit produced by chemotherapy. Evidence of mitochondrial transfer in the nervous system has also been visualized in terms of cornea damage and repair. Jiang et al. showed that rotenone-induced-oxidative-stress-treated corneal epithelia cells were permissible to MSCs-derived mitochondrial transfer via tubular connections. In his research, he was able to demonstrate a conferred protective capacity of mitochondria on corneal epithelial cells upon rotenone treatment, as cells’ respiratory capacity increased. In addition, MSCs’ transplantation into the alkali-eye of a rabbit model promoted corneal epithelial cells’ wound-healing capacity [180]. These results, further, support the notion of MSCs’ beneficial effects in the clinic and the potential therapeutic effects of functional mitochondrial donation.

The other side of mitochondria transfer: an increased malignancy in cancer cells

MSCs play an important role in tumor microenvironment and cancer progression, as they have been associated with poor outcomes in patients [181–185]. MSCs’ deleterious presence in tumors has been related to multiple cancers, including breast and prostate [186, 187]. It has been observed that MSCs are attracted to the tumor site by inflammatory signals [181]. MSCs not only secrete immune-regulatory cytokines promoting tumor immune escape, but also are engulfed by breast cancer cells enhancing its epithelial to promote mesenchymal transition (EMT), stemness, invasion, and metastasis [186–188]. Many cancer cells, such as AML and melanoma cells, are dependent on their mitochondrial function to survive and have been shown to interact with MSCs [189, 190]. MSCs can transfer mitochondria by TNTs and vesicles to breast, acute myeloid leukemia (AML) and ovarian cancer cells, inducing an increase in migration, invasion, proliferation, production of ATP and resistance to chemotherapeutic agents [138, 189, 191–193]. It has been observed that the production of NADPH oxidase-2 derived superoxide by AML stimulates MSC mitogenesis by activating PGC-1α, and thus the transfer of mitochondria to AML cells [194]. In addition, tumor macrophages that rely on respiration and mitochondria function instead of glycolysis induce an anti-inflammatory effect, helping cancer to survive immune recognition and attack [195]. Warburgs’ first observations on cancer showed that malignant cells prefer glycolysis even in aerobic conditions. However, recent advances in the understanding of tumor microenvironment metabolism have shown that cancer and other tumor resident cells need mitochondria to survive and develop [196]. The mitochondrial transfer among cells, especially from MSCs to cancer cells, is a key process in the tumor providing metabolic flexibility and chemotherapy resistance [196].

The tumor is a metabolically complex microenvironment divided into cellular compartments [197]. In the first compartment, fibroblasts could undergo mitophagy and mitochondrial dysfunction, leading to glycolysis causing lactate production and ketone body accumulation [198, 199]. In the other compartment, cancer cells use these molecules to sustain constant growth, as they are able to produce mitochondria, which help them to metabolize nutrients and produce the building blocks for growth [197]. It is important to determine how MSCs interact with cells in a specific glycolytic or oxidative tumor compartment or if they belong to a particular one. MSC activation may or may not lead to an increase in the transfer of mitochondria, a process still poorly understood. In each of these scenarios, it is essential to know what cells are involved and in which compartment they receive mitochondria from MSCs. For instance, the use of artificial mitochondria transfer, with techniques such as MitoCeption, could help improve the understanding of the sole effect of mitochondrial transfer and dynamics inside cells and tumors. MSC mitochondria could be tagged to determine which tumor cells they connect. Later, cancer cells or immune cells could be MitoCepted ex vivo with MSC mitochondria. Then, these cells could be transferred to a tumor microenvironment to understand the effects of the transfer of mitochondria on different tumors. The comprehension of the role of mitochondria in these scenarios would help in the development of new therapies.

Limitations and future perspectives

Knowing the potential of MSCs for cell regulation and regeneration added to the broad applications of mitochondrial transfer and potentially free circulating mitochondria, these findings widen the field of clinical application for MSCs and MSCs-derived mitochondrial transfer directly onto target cells.

Mitochondria can be transferred to targeted cells and tissues by three means: in vitro, ex vivo and in situ to the affected site and systemically [33, 34, 136, 193, 200–202]. The in vitro/ex vivo transfer of mitochondria offers a wide range of applications as cells could be isolated from a patient, modified by the mitochondria transfer and reintroduced into the affected site, in a similar process to the generation of CART cells [135, 193, 203]. It would be possible to transfer mitochondria to improve the survival of cells during culture before being administered to a patient. Primary allogeneic mitochondrial mix (PAMM) MitoCeption is an easy-to-apply procedure to transfer mitochondria to fresh and primary immune cells, and this process has been shown to reduce PBMCs stress after UVR-induced damage [135]. Furthermore, MSCs could be amplified in the laboratory and MitoCepted to improve metabolic processes such as respiration, ATP production, fatty-acid oxidation, possibly priming MSCs to secrete a higher quantity of regenerative factors2 [34]. Recently, a simple, high-throughput device, called MitoPunch, was developed for transferring isolated mitochondria into mammalian cells [204]. This pressure-driven method allows the transfer of mitochondria into 100,000 or more recipient cells simultaneously, which is a significant improvement from existing mitochondrial transfer technologies. This approach enables researchers to tailor a key genetic component of cells, to study and potentially treat debilitating diseases such as cancer, diabetes and metabolic disorders.

On the other hand, Cell Educator Therapy, a technique that consists in “educating” cells outside and reintroducing them into the target system [205], possesses a suitable and safer idea to use with mitochondria as treatment. The most used and studied application of mitochondria transfer is in situ injection [206]. Numerous studies have shown that mitochondria are taken up by tissue resident cells in the damaged site [29]. This has helped various cells and tissues to recover after ischemia ranging from mice and rabbit models to a recruiting phase I clinical application (clinicaltrials.gov) [202, 206]. The systemic administration of mitochondria is a third option to transfer them to a patient. However, it has been reported that this method results in only a few mitochondria arriving at the injured site and showing positive effects [206, 207]. Recent evidence demonstrates that mitochondria could exist outside cells and persist in circulation under physiological conditions [162]. If extracellular mitochondria exist physiologically in the body, the administration of mitochondria systemically would add to the already existing mitochondria in circulation. Thus, increasing the likelihood of mitochondria arriving at the desired tissue. Understanding the role of physiological existing extracellular mitochondria in circulation could help improve the administration and application of mitochondrial transfer.

Active extracellular mitochondria do not seem to generate an immune response when they are nude or wrapped in a membrane [33]. It has been mentioned that the extracellular milieu could affect nude mitochondria viability, which is a major concern when they are going to be applied systemically [165]. Artificially wrapping mitochondria in a phospholipid membrane could be a plausible approach to extend the activity of mitochondria in circulation [34]. However, cells in our system could react differently to nude and membrane-wrapped mitochondria. The amount of nude or wrapped mitochondria in circulation could vary during a pathological process or aging. It is still unknown if the wrapping of mitochondria functions as a protective mechanism to cellular stress or promotes disease progression. Damaged mitochondria and their content issued from apoptotic or necrotic cells are recognized by immune cells as DAMPs [143]. In diseases like sepsis, both active and damaged mitochondria could coexist, which is an important aspect to comprehend how they interact with cells in our body to propose new therapeutic approaches.

Final remarks

The use of mitochondria derived from MSCs or other cells for therapeutic purposes represents an innovative tool to treat many diseases (immune deregulation, inflammation-related disorders, wound healing, ischemic events, and aging) with an increasing amount of promising evidence, ranging from preclinical to clinical research. Furthermore, the eventual reversal, induced by the mitochondrial transfer, of the metabolic and pro-inflammatory profile, will open new avenues to the understanding of diseases etiology, their relation to both systemic and local risk factors, and also lead to new therapeutic tools for the control of inflammatory and degenerative diseases.

Author contributions

FV, YH, and MK were involved in reading and editing the manuscript. All the authors drafted the manuscript and approved the final version.

Funding

This work was supported by grants from the Chilean National Agency for Investigation and Development: ANID (Agencia Nacional de Investigación y Desarrollo) FONDECYT Regular #1211749 and FONDECYT de Iniciación #11221017, and by ANID—Basal funding for Scientific and Technological Center of Excellence, IMPACT, #FB210024.

Data availability

Not applicable.

Code availability

Not applicable.

Declarations

Conflict of interest

MK is the chief scientific officer of Cells for Cells and Regenero, the Chilean consortium for regenerative medicine. YH received a stipend from Regenero. AC is the chief executive officer of Dragon BioMed with spin-off of the Universidad San Francisco de Quito in regenerative medicine. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Yessia Hidalgo, Email: yhidalgo@regenero.cl.

Maroun Khoury, Email: mkhoury@uandes.cl.

References

1.Pittenger MF. Multilineage potential of adult human mesenchymal stem cells. Science (80-) 1999;284:143–147. doi: 10.1126/science.284.5411.143. [DOI] [PubMed] [Google Scholar]
2.Krampera M, Franchini M, Pizzolo G, Aprili G. Mesenchymal stem cells: from biology to clinical use. Blood Transfus. 2007;5:120–129. doi: 10.2450/2007.0029-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
3.He A, Jiang Y, Gui C, et al. The antiapoptotic effect of mesenchymal stem cell transplantation on ischemic myocardium is enhanced by anoxic preconditioning. Can J Cardiol. 2009;25:353–358. doi: 10.1016/s0828-282x(09)70094-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
4.Block GJ, Ohkouchi S, Fung F, et al. Multipotent stromal cells are activated to reduce apoptosis in part by upregulation and secretion of stanniocalcin-1. Stem Cells. 2009;27:670–681. doi: 10.1002/stem.20080742. [DOI] [PMC free article] [PubMed] [Google Scholar]
5.Weiss ARR, Dahlke MH. Immunomodulation by mesenchymal stem cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs. Front Immunol. 2019;10:1191. doi: 10.3389/fimmu.2019.01191. [DOI] [PMC free article] [PubMed] [Google Scholar]
6.Oh JY, Kim MK, Shin MS, et al. The anti-inflammatory and anti-angiogenic role of mesenchymal stem cells in corneal wound healing following chemical injury. Stem Cells. 2008;26:1047–1055. doi: 10.1634/stemcells.2007-0737. [DOI] [PubMed] [Google Scholar]
7.Zhang R, Liu Y, Yan K, et al. Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury. J Neuroinflammation. 2013;10:871. doi: 10.1186/1742-2094-10-106. [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Abdi R, Fiorina P, Adra CN, et al. Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes. Diabetes. 2008;57:1759–1767. doi: 10.2337/db08-0180. [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Wang M, Yuan Q, Xie L. Mesenchymal stem cell-based immunomodulation: properties and clinical application. Stem Cells Int. 2018;2018:1–12. doi: 10.1155/2018/3057624. [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Wang L-T, Ting C-H, Yen M-L, et al. Human mesenchymal stem cells (MSCs) for treatment towards immune- and inflammation-mediated diseases: review of current clinical trials. J Biomed Sci. 2016;23:76. doi: 10.1186/s12929-016-0289-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
11.Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105:1815–1822. doi: 10.1182/blood-2004-04-1559. [DOI] [PubMed] [Google Scholar]
12.Kinnaird T, Stabile E, Burnett MS, et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res. 2004;94:678–685. doi: 10.1161/01.RES.0000118601.37875.AC. [DOI] [PubMed] [Google Scholar]
13.Chen J, Li Y, Katakowski M, et al. Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res. 2003;73:778–786. doi: 10.1002/jnr.10691. [DOI] [PubMed] [Google Scholar]
14.Laflamme MA, Murry CE. Regenerating the heart. Nat Biotechnol. 2005;23:845–856. doi: 10.1038/nbt1117. [DOI] [PubMed] [Google Scholar]
15.Murphy JM, Fink DJ, Hunziker EB, Barry FP. Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum. 2003;48:3464–3474. doi: 10.1002/art.11365. [DOI] [PubMed] [Google Scholar]
16.Fellows CR, Matta C, Zakany R, et al. Adipose, bone marrow and synovial joint-derived mesenchymal stem cells for cartilage repair. Front Genet. 2016;7:213. doi: 10.3389/fgene.2016.00213. [DOI] [PMC free article] [PubMed] [Google Scholar]
17.Barry F, Murphy M. Mesenchymal stem cells in joint disease and repair. Nat Rev Rheumatol. 2013;9:584–594. doi: 10.1038/nrrheum.2013.109. [DOI] [PubMed] [Google Scholar]
18.Morrison TJ, Jackson MV, Cunningham EK, et al. Mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer. Am J Respir Crit Care Med. 2017;196:1275–1286. doi: 10.1164/rccm.201701-0170OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Tisato V, Naresh K, Girdlestone J, et al. Mesenchymal stem cells of cord blood origin are effective at preventing but not treating graft-versus-host disease. Leukemia. 2007;21:1992–1999. doi: 10.1038/sj.leu.2404847. [DOI] [PubMed] [Google Scholar]
20.Wang L, Zhu C, Ma D, et al. Efficacy and safety of mesenchymal stromal cells for the prophylaxis of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: a meta-analysis of randomized controlled trials. Ann Hematol. 2018;97:1941–1950. doi: 10.1007/s00277-018-3384-8. [DOI] [PubMed] [Google Scholar]
21.Leibacher J, Henschler R. Biodistribution, migration and homing of systemically applied mesenchymal stem/stromal cells. Stem Cell Res Ther. 2016;7:7. doi: 10.1186/s13287-015-0271-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
22.Chen L, Tredget EE, Wu PYG, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS ONE. 2008;3:e1886. doi: 10.1371/journal.pone.0001886. [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Morrison DE, Aitken JB, de Jonge MD, et al. High mitochondrial accumulation of new gadolinium(III) agents within tumour cells. Chem Commun (Camb) 2014;50:2252–2254. doi: 10.1039/c3cc46903d. [DOI] [PubMed] [Google Scholar]
24.Islam MN, Das SR, Emin MT, et al. Mitochondrial transfer from bone-marrow–derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med. 2012;18:759–765. doi: 10.1038/nm.2736. [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Jackson MV, Morrison TJ, Doherty DF, et al. Mitochondrial transfer via tunneling nanotubes is an important mechanism by which mesenchymal stem cells enhance macrophage phagocytosis in the in vitro and in vivo models of ARDS. Stem Cells. 2016;34:2210–2223. doi: 10.1002/stem.2372. [DOI] [PMC free article] [PubMed] [Google Scholar]
26.Acquistapace A, Bru T, Lesault P-F, et al. Human mesenchymal stem cells reprogram adult cardiomyocytes toward a progenitor-like state through partial cell fusion and mitochondria transfer. Stem Cells. 2011;29:812–824. doi: 10.1002/stem.632. [DOI] [PMC free article] [PubMed] [Google Scholar]
27.Huda F, Fan Y, Suzuki M, et al. Fusion of human fetal mesenchymal stem cells with “degenerating” cerebellar neurons in spinocerebellar ataxia type 1 model mice. PLoS ONE. 2016;11:e0164202. doi: 10.1371/journal.pone.0164202. [DOI] [PMC free article] [PubMed] [Google Scholar]
28.Emani SM, McCully JD. Mitochondrial transplantation: applications for pediatric patients with congenital heart disease. Transl Pediatr. 2018;7:169–175. doi: 10.21037/tp.2018.02.02. [DOI] [PMC free article] [PubMed] [Google Scholar]
29.Ramirez-Barbieri G, Moskowitzova K, Shin B, et al. Alloreactivity and allorecognition of syngeneic and allogeneic mitochondria. Mitochondrion. 2019;46:103–115. doi: 10.1016/j.mito.2018.03.002. [DOI] [PubMed] [Google Scholar]
30.Clark MA, Shay JW. Mitochondrial transformation of mammalian cells. Nature. 1982;295:605–607. doi: 10.1038/295605a0. [DOI] [PubMed] [Google Scholar]
31.Rustom A, Saffrich R, Markovic I, et al. Nanotubular highways for intercellular organelle transport. Science (80-) 2004;303:1007–1010. doi: 10.1126/science.1093133. [DOI] [PubMed] [Google Scholar]
32.Gerdes H-H, Bukoreshtliev NV, Barroso JFV. Tunneling nanotubes: a new route for the exchange of components between animal cells. FEBS Lett. 2007;581:2194–2201. doi: 10.1016/j.febslet.2007.03.071. [DOI] [PubMed] [Google Scholar]
33.Miliotis S, Nicolalde B, Ortega M, et al. Forms of extracellular mitochondria and their impact in health. Mitochondrion. 2019;48:16–30. doi: 10.1016/j.mito.2019.02.002. [DOI] [PubMed] [Google Scholar]
34.Caicedo A, Aponte PM, Cabrera F, et al. Artificial mitochondria transfer: current challenges, advances, and future applications. Stem Cells Int. 2017;2017:1–23. doi: 10.1155/2017/7610414. [DOI] [PMC free article] [PubMed] [Google Scholar]
35.Spees JL, Olson SD, Whitney MJ, Prockop DJ. Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci USA. 2006;103:1283–1288. doi: 10.1073/pnas.0510511103. [DOI] [PMC free article] [PubMed] [Google Scholar]
36.Pittenger MF, Discher DE, Péault BM, et al. Mesenchymal stem cell perspective: cell biology to clinical progress. npj Regen Med. 2019;4:22. doi: 10.1038/s41536-019-0083-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
37.Bartolucci J, Verdugo FJ, González PL, et al. Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure. Circ Res. 2017;121:1192–1204. doi: 10.1161/CIRCRESAHA.117.310712. [DOI] [PMC free article] [PubMed] [Google Scholar]
38.Matas J, Orrego M, Amenabar D, et al. Umbilical cord-derived mesenchymal stromal cells (MSCs) for knee osteoarthritis: repeated MSC dosing is superior to a single MSC dose and to hyaluronic acid in a controlled randomized phase I/II trial. Stem Cells Transl Med. 2018;8:215–224. doi: 10.1002/sctm.18-0053. [DOI] [PMC free article] [PubMed] [Google Scholar]
39.Caplan H, Olson SD, Kumar A, et al. Mesenchymal stromal cell therapeutic delivery: translational challenges to clinical application. Front Immunol. 2019;10:1645. doi: 10.3389/fimmu.2019.01645. [DOI] [PMC free article] [PubMed] [Google Scholar]
40.Couto PS, Shatirishvili G, Bersenev A, Verter F. First decade of clinical trials and published studies with mesenchymal stromal cells from umbilical cord tissue. Regen Med. 2019;14:309–319. doi: 10.2217/rme-2018-0171. [DOI] [PubMed] [Google Scholar]
41.Kurte M, Vega-Letter AM, Luz-Crawford P, et al. Time-dependent LPS exposure commands MSC immunoplasticity through TLR4 activation leading to opposite therapeutic outcome in EAE. Stem Cell Res Ther. 2020;11:416. doi: 10.1186/s13287-020-01840-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
42.Velarde F, Castañeda V, Morales E, et al. Use of human umbilical cord and its byproducts in tissue regeneration. Front Bioeng Biotechnol. 2020;8:117. doi: 10.3389/fbioe.2020.00117. [DOI] [PMC free article] [PubMed] [Google Scholar]
43.Fan C-G, Zhang Q, Zhou J. Therapeutic potentials of mesenchymal stem cells derived from human umbilical cord. Stem Cell Rev Reports. 2011;7:195–207. doi: 10.1007/s12015-010-9168-8. [DOI] [PubMed] [Google Scholar]
44.Veryasov VN, Savilova AM, Buyanovskaya OA, et al. Isolation of mesenchymal stromal cells from extraembryonic tissues and their characteristics. Bull Exp Biol Med. 2014;157:119–124. doi: 10.1007/s10517-014-2506-0. [DOI] [PubMed] [Google Scholar]
45.Mabuchi Y, Matsuzaki Y. Prospective isolation of resident adult human mesenchymal stem cell population from multiple organs. Int J Hematol. 2016;103:138–144. doi: 10.1007/s12185-015-1921-y. [DOI] [PubMed] [Google Scholar]
46.Laroye C, Gauthier M, Antonot H, et al. Mesenchymal stem/stromal cell production compliant with good manufacturing practice: comparison between bone marrow, the gold standard adult source, and Wharton’s Jelly, an extraembryonic source. J Clin Med. 2019;8:2207. doi: 10.3390/jcm8122207. [DOI] [PMC free article] [PubMed] [Google Scholar]
47.Du WJ, Chi Y, Yang ZX, et al. Heterogeneity of proangiogenic features in mesenchymal stem cells derived from bone marrow, adipose tissue, umbilical cord, and placenta. Stem Cell Res Ther. 2016;7:163. doi: 10.1186/s13287-016-0418-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
48.Ertl J, Pichlsberger M, Tuca A-C, et al. Comparative study of regenerative effects of mesenchymal stem cells derived from placental amnion, chorion and umbilical cord on dermal wounds. Placenta. 2018;65:37–46. doi: 10.1016/j.placenta.2018.04.004. [DOI] [PubMed] [Google Scholar]
49.Wu M, Zhang R, Zou Q, et al. Comparison of the biological characteristics of mesenchymal stem cells derived from the human placenta and umbilical cord. Sci Rep. 2018;8:5014. doi: 10.1038/s41598-018-23396-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
50.Deng Y, Zhang Y, Ye L, et al. Umbilical cord-derived mesenchymal stem cells instruct monocytes towards an il10-producing phenotype by secreting IL6 and HGF. Sci Rep. 2016;6:37566. doi: 10.1038/srep37566. [DOI] [PMC free article] [PubMed] [Google Scholar]
51.Kern S, Eichler H, Stoeve J, et al. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells. 2006;24:1294–1301. doi: 10.1634/stemcells.2005-0342. [DOI] [PubMed] [Google Scholar]
52.Mizukami A, Swiech K. Mesenchymal stromal cells: from discovery to manufacturing and commercialization. Stem Cells Int. 2018;2018:1–13. doi: 10.1155/2018/4083921. [DOI] [PMC free article] [PubMed] [Google Scholar]
53.Li R, Li X-M, Chen J-R. Clinical efficacy and safety of autologous stem cell transplantation for patients with ST-segment elevation myocardial infarction. Ther Clin Risk Manag. 2016;12:1171–1189. doi: 10.2147/TCRM.S107199. [DOI] [PMC free article] [PubMed] [Google Scholar]
54.Murata M, Teshima T. Treatment of steroid-refractory acute graft-versus-host disease using commercial mesenchymal stem cell products. Front Immunol. 2021;12:724380. doi: 10.3389/fimmu.2021.724380. [DOI] [PMC free article] [PubMed] [Google Scholar]
55.Gebara N, Rossi A, Skovronova R, et al. Extracellular vesicles, apoptotic bodies and mitochondria: stem cell bioproducts for organ regeneration. Curr Transplant Reports. 2020;7:105–113. doi: 10.1007/s40472-020-00282-2. [DOI] [Google Scholar]
56.Yeo RWY, Lai RC, Zhang B, et al. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev. 2013;65:336–341. doi: 10.1016/j.addr.2012.07.001. [DOI] [PubMed] [Google Scholar]
57.Mendt M, Rezvani K, Shpall E. Mesenchymal stem cell-derived exosomes for clinical use. Bone Marrow Transplant. 2019;54:789–792. doi: 10.1038/s41409-019-0616-z. [DOI] [PubMed] [Google Scholar]
58.Alcayaga-Miranda F, Varas-Godoy M, Khoury M. Harnessing the angiogenic potential of stem cell-derived exosomes for vascular regeneration. Stem Cells Int. 2016;2016:1–11. doi: 10.1155/2016/3409169. [DOI] [PMC free article] [PubMed] [Google Scholar]
59.Squillaro T, Peluso G, Galderisi U. Clinical trials with mesenchymal stem cells: an update. Cell Transplant. 2016;25:829–848. doi: 10.3727/096368915X689622. [DOI] [PubMed] [Google Scholar]
60.Lai RC, Tan SS, Teh BJ, et al. Proteolytic potential of the MSC exosome proteome: implications for an exosome-mediated delivery of therapeutic proteasome. Int J Proteomics. 2012;2012:1–14. doi: 10.1155/2012/971907. [DOI] [PMC free article] [PubMed] [Google Scholar]
61.Nassar W, El-Ansary M, Sabry D, et al. Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases. Biomater Res. 2016;20:21. doi: 10.1186/s40824-016-0068-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
62.Yosef OB, Jacoby E, Gruber N, et al. Promising results for kearns-sayre syndrome of first in man treatment by mitochondrial augmentation therapy (457) Neurology. 2020;94:457. [Google Scholar]
63.Almannai M, El-Hattab AW, Ali M, et al. Clinical trials in mitochondrial disorders, an update. Mol Genet Metab. 2020;131:1–13. doi: 10.1016/j.ymgme.2020.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
64.Bottani E, Lamperti C, Prigione A, et al. Therapeutic approaches to treat mitochondrial diseases: “one-size-fits-all” and “precision medicine” strategies. Pharmaceutics. 2020;12:1083. doi: 10.3390/pharmaceutics12111083. [DOI] [PMC free article] [PubMed] [Google Scholar]
65.Nicolás-Ávila JA, Lechuga-Vieco AV, Esteban-Martínez L, et al. A network of macrophages supports mitochondrial homeostasis in the heart. Cell. 2020;183:94–109.e23. doi: 10.1016/j.cell.2020.08.031. [DOI] [PubMed] [Google Scholar]
66.Brestoff JR, Wilen CB, Moley JR, et al. Intercellular mitochondria transfer to macrophages regulates white adipose tissue homeostasis and is impaired in obesity. Cell Metab. 2021;33:270–282.e8. doi: 10.1016/j.cmet.2020.11.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
67.Crewe C, Funcke J-B, Li S, et al. Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes. Cell Metab. 2021;33:1853–1868.e11. doi: 10.1016/j.cmet.2021.08.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
68.Rodriguez A-M, Nakhle J, Griessinger E, Vignais M-L. Intercellular mitochondria trafficking highlighting the dual role of mesenchymal stem cells as both sensors and rescuers of tissue injury. Cell Cycle. 2018;17:712–721. doi: 10.1080/15384101.2018.1445906. [DOI] [PMC free article] [PubMed] [Google Scholar]
69.Li C, Cheung MKH, Han S, et al. Mesenchymal stem cells and their mitochondrial transfer: a double-edged sword. Biosci Rep. 2019;39:BSR20182417. doi: 10.1042/BSR20182417. [DOI] [PMC free article] [PubMed] [Google Scholar]
70.Schulze A, Harris AL. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature. 2012;491:364–373. doi: 10.1038/nature11706. [DOI] [PubMed] [Google Scholar]
71.Ahmad T, Mukherjee S, Pattnaik B, et al. Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy. EMBO J. 2014;33:994–1010. doi: 10.1002/embj.201386030. [DOI] [PMC free article] [PubMed] [Google Scholar]
72.Court AC, Le-Gatt A, Luz-Crawford P, et al. Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response. EMBO Rep. 2020;21:e48052. doi: 10.15252/embr.201948052. [DOI] [PMC free article] [PubMed] [Google Scholar]
73.Phinney DG, Di Giuseppe M, Njah J, et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015;6:8472. doi: 10.1038/ncomms9472. [DOI] [PMC free article] [PubMed] [Google Scholar]
74.Puhm F, Afonyushkin T, Resch U, et al. Mitochondria are a subset of extracellular vesicles released by activated monocytes and induce type I IFN and TNF responses in endothelial cells. Circ Res. 2019;125:43–52. doi: 10.1161/CIRCRESAHA.118.314601. [DOI] [PubMed] [Google Scholar]
75.Boudreau LH, Duchez A, Cloutier N, et al. Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A 2 to promote in fl ammation. Blood. 2019;124:2173–2184. doi: 10.1182/blood-2014-05-573543.A.-C.D. [DOI] [PMC free article] [PubMed] [Google Scholar]
76.Shi Y, Wang Y, Li Q, et al. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases. Nat Rev Nephrol. 2018;14:493–507. doi: 10.1038/s41581-018-0023-5. [DOI] [PubMed] [Google Scholar]
77.Mistry JJ, Marlein CR, Moore JA, et al. ROS-mediated PI3K activation drives mitochondrial transfer from stromal cells to hematopoietic stem cells in response to infection. Proc Natl Acad Sci USA. 2019;116:24610–24619. doi: 10.1073/pnas.1913278116. [DOI] [PMC free article] [PubMed] [Google Scholar]
78.Hofmann AD, Beyer M, Krause-Buchholz U, et al. Oxphos supercomplexes as a hallmark of the mitochondrial phenotype of adipogenic differentiated human MSCS. PLoS ONE. 2012;7:e35160. doi: 10.1371/journal.pone.0035160. [DOI] [PMC free article] [PubMed] [Google Scholar]
79.Li Q, Gao Z, Chen Y. The role of mitochondria in osteogenic, adipogenic and chondrogenic differentiation of mesenchymal stem cells. Protein Cell. 2017;8:439–445. doi: 10.1007/s13238-017-0385-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
80.Bertolo A, Capossela S, Fränkl G, et al. Oxidative status predicts quality in human mesenchymal stem cells. Stem Cell Res Ther. 2017;8:1–13. doi: 10.1186/s13287-016-0452-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
81.Wang W, Zhang Y, Lu W, Liu K. Mitochondrial reactive oxygen species regulate adipocyte differentiation of mesenchymal stem cells in hematopoietic stress induced by arabinosylcytosine. PLoS ONE. 2015;10:e0120629. doi: 10.1371/journal.pone.0120629. [DOI] [PMC free article] [PubMed] [Google Scholar]
82.Tan J, Xu X, Tong Z, et al. Decreased osteogenesis of adult mesenchymal stem cells by reactive oxygen species under cyclic stretch: a possible mechanism of age related osteoporosis. Bone Res. 2015;3:1–6. doi: 10.1038/boneres.2015.3. [DOI] [PMC free article] [PubMed] [Google Scholar]
83.Kanda Y, Hinata T, Kang SW, Watanabe Y. Reactive oxygen species mediate adipocyte differentiation in mesenchymal stem cells. Life Sci. 2011;89:250–258. doi: 10.1016/j.lfs.2011.06.007. [DOI] [PubMed] [Google Scholar]
84.Chen C-T, Shih Y-RV, Kuo TK, et al. Coordinated changes of mitochondrial biogenesis and antioxidant enzymes during osteogenic differentiation of human mesenchymal stem cells. Stem Cells. 2008;26:960–968. doi: 10.1634/stemcells.2007-0509. [DOI] [PubMed] [Google Scholar]
85.Shum LC, White NS, Mills BN, et al. Energy metabolism in mesenchymal. Stem Cells. 2016;25:114–122. doi: 10.1089/scd.2015.0193. [DOI] [PMC free article] [PubMed] [Google Scholar]
86.Zhang Y, Marsboom G, Toth PT, Rehman J. Mitochondrial respiration regulates adipogenic differentiation of human mesenchymal stem cells. PLoS ONE. 2013;8:e77077. doi: 10.1371/journal.pone.0077077. [DOI] [PMC free article] [PubMed] [Google Scholar]
87.Pattappa G, Heywood HK, de Bruijn JD, Lee DA. The metabolism of human mesenchymal stem cells during proliferation and differentiation. J Cell Physiol. 2011;226:2562–2570. doi: 10.1002/jcp.22605. [DOI] [PubMed] [Google Scholar]
88.Chiu SP, Lee YW, Wu LY, et al. Application of ECIS to assess FCCP-induced changes of MSC micromotion and wound healing migration. Sensors (Switzerland) 2019;19:3210. doi: 10.3390/s19143210. [DOI] [PMC free article] [PubMed] [Google Scholar]
89.Mancini OK, Lora M, Cuillerier A, et al. Mitochondrial oxidative stress reduces the immunopotency of mesenchymal stromal cells in adults with coronary artery disease. Circ Res. 2018;122:255–266. doi: 10.1161/CIRCRESAHA.117.311400. [DOI] [PubMed] [Google Scholar]
90.Guo Y, Chi X, Wang Y, et al. Mitochondria transfer enhances proliferation, migration, and osteogenic differentiation of bone marrow mesenchymal stem cell and promotes bone defect healing. Stem Cell Res Ther. 2020;11:245. doi: 10.1186/s13287-020-01704-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
91.Paliwal S, Chaudhuri R, Agrawal A, Mohanty S. Human tissue-specific MSCs demonstrate differential mitochondria transfer abilities that may determine their regenerative abilities. Stem Cell Res Ther. 2018;9:298. doi: 10.1186/s13287-018-1012-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
92.Kitani T, Kami D, Matoba S, Gojo S. Internalization of isolated functional mitochondria: involvement of macropinocytosis. J Cell Mol Med. 2014;18:1694–1703. doi: 10.1111/jcmm.12316. [DOI] [PMC free article] [PubMed] [Google Scholar]
93.Zhao Y, Jiang Z, Delgado E, et al. Platelet-derived mitochondria display embryonic stem cell markers and improve pancreatic islet β-cell function in humans. Stem Cells Transl Med. 2017;6:1684–1697. doi: 10.1002/sctm.17-0078. [DOI] [PMC free article] [PubMed] [Google Scholar]
94.Duroux-Richard I, Apparailly F, Khoury M. Mitochondrial microRNAs contribute to macrophage immune functions including differentiation, polarization, and activation. Front Physiol. 2021;12:738140. doi: 10.3389/fphys.2021.738140. [DOI] [PMC free article] [PubMed] [Google Scholar]
95.Vafai SB, Mootha VK. Mitochondrial disorders as windows into an ancient organelle. Nature. 2012;491:374–383. doi: 10.1038/nature11707. [DOI] [PubMed] [Google Scholar]
96.McBride HM, Neuspiel M, Wasiak S. Mitochondria: more than just a powerhouse. Curr Biol. 2006;16:R551–R560. doi: 10.1016/j.cub.2006.06.054. [DOI] [PubMed] [Google Scholar]
97.Roger AJ, Muñoz-Gómez SA, Kamikawa R. The origin and diversification of mitochondria. Curr Biol. 2017;27:R1177–R1192. doi: 10.1016/j.cub.2017.09.015. [DOI] [PubMed] [Google Scholar]
98.Riley JS, Tait SW. Mitochondrial DNA in inflammation and immunity. EMBO Rep. 2020;21:e49799. doi: 10.15252/embr.201949799. [DOI] [PMC free article] [PubMed] [Google Scholar]
99.Tiku V, Tan M-W, Dikic I. Mitochondrial functions in infection and immunity. Trends Cell Biol. 2020;30:263–275. doi: 10.1016/j.tcb.2020.01.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
100.Peña-Blanco A, García-Sáez AJ. Bax, Bak and beyond—mitochondrial performance in apoptosis. FEBS J. 2018;285:416–431. doi: 10.1111/febs.14186. [DOI] [PubMed] [Google Scholar]
101.Sarasija S, Norman KR. A γ-secretase independent role for presenilin in calcium homeostasis impacts mitochondrial function and morphology in caenorhabditis elegans. Genetics. 2015;201:1453–1466. doi: 10.1534/genetics.115.182808. [DOI] [PMC free article] [PubMed] [Google Scholar]
102.Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell. 2012;148:1145–1159. doi: 10.1016/j.cell.2012.02.035. [DOI] [PMC free article] [PubMed] [Google Scholar]
103.Tilokani L, Nagashima S, Paupe V, Prudent J. Mitochondrial dynamics: overview of molecular mechanisms. Essays Biochem. 2018;62:341–360. doi: 10.1042/EBC20170104. [DOI] [PMC free article] [PubMed] [Google Scholar]
104.Liesa M, Palacín M, Zorzano A. Mitochondrial dynamics in mammalian health and disease. Physiol Rev. 2009;89:799–845. doi: 10.1152/physrev.00030.2008. [DOI] [PubMed] [Google Scholar]
105.Pernas L, Scorrano L. Mito-morphosis: mitochondrial fusion, fission, and cristae remodeling as key mediators of cellular function. Annu Rev Physiol. 2016;78:505–531. doi: 10.1146/annurev-physiol-021115-105011. [DOI] [PubMed] [Google Scholar]
106.Wai T, Langer T. Mitochondrial dynamics and metabolic regulation. Trends Endocrinol Metab. 2016;27:105–117. doi: 10.1016/j.tem.2015.12.001. [DOI] [PubMed] [Google Scholar]
107.Pickles S, Vigié P, Youle RJ. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol. 2018;28:R170–R185. doi: 10.1016/j.cub.2018.01.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
108.Dominy JE, Puigserver P. Mitochondrial biogenesis through activation of nuclear signaling proteins. Cold Spring Harb Perspect Biol. 2013;5:1–16. doi: 10.1101/cshperspect.a015008. [DOI] [PMC free article] [PubMed] [Google Scholar]
109.Giacomello M, Pyakurel A, Glytsou C, Scorrano L. The cell biology of mitochondrial dynamics. Nat Rev Mol Cell Biol. 2020;21:204–224. doi: 10.1038/s41580-020-0210-7. [DOI] [PubMed] [Google Scholar]
110.Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr. 2011;93:884S–890S. doi: 10.3945/ajcn.110.001917. [DOI] [PMC free article] [PubMed] [Google Scholar]
111.Luo C, Widlund HR, Puigserver P. PGC-1 coactivators: shepherding the mitochondrial biogenesis of tumors. Trends Cancer. 2016;2:619–631. doi: 10.1016/j.trecan.2016.09.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
112.Scarpulla RC. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta - Mol Cell Res. 2011;1813:1269–1278. doi: 10.1016/j.bbamcr.2010.09.019. [DOI] [PMC free article] [PubMed] [Google Scholar]
113.Price NL, Gomes AP, Ling AJY, et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 2012;15:675–690. doi: 10.1016/j.cmet.2012.04.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
114.Jin SM, Youle RJ. PINK1-and Parkin-mediated mitophagy at a glance. J Cell Sci. 2012;125:795–799. doi: 10.1242/jcs.093849. [DOI] [PMC free article] [PubMed] [Google Scholar]
115.Sato S, Furuya N (2017) Induction of PINK1/Parkin-Mediated Mitophagy. In: Methods in molecular biology. Humana Press Inc., pp 9–17
116.Palikaras K, Lionaki E, Tavernarakis N. Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. Nat Cell Biol. 2018;20:1013–1022. doi: 10.1038/s41556-018-0176-2. [DOI] [PubMed] [Google Scholar]
117.Yoshii SR, Kishi C, Ishihara N, Mizushima N. Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane. J Biol Chem. 2011;286:19630–19640. doi: 10.1074/jbc.M110.209338. [DOI] [PMC free article] [PubMed] [Google Scholar]
118.Saito T, Sadoshima J. Molecular mechanisms of mitochondrial autophagy/mitophagy in the heart. Circ Res. 2015;116:1477–1490. doi: 10.1161/CIRCRESAHA.116.303790. [DOI] [PMC free article] [PubMed] [Google Scholar]
119.Jorgensen C, Khoury M. Musculoskeletal progenitor/stromal cell-derived mitochondria modulate cell differentiation and therapeutical function. Front Immunol. 2021;12:606781. doi: 10.3389/fimmu.2021.606781. [DOI] [PMC free article] [PubMed] [Google Scholar]
120.Fillmore N, Huqi A, Jaswal JS, et al. Effect of fatty acids on human bone marrow mesenchymal stem cell energy metabolism and survival. PLoS ONE. 2015;10:e0120257. doi: 10.1371/journal.pone.0120257. [DOI] [PMC free article] [PubMed] [Google Scholar]
121.Shum LC, White NS, Mills BN, et al. Energy metabolism in mesenchymal stem cells during osteogenic differentiation. Stem Cells Dev. 2016;25:114–122. doi: 10.1089/scd.2015.0193. [DOI] [PMC free article] [PubMed] [Google Scholar]
122.Lee JH, Yoon YM, Lee SH. Hypoxic preconditioning promotes the bioactivities of mesenchymal stem cells via the HIF-1α-GRP78-Akt axis. Int J Mol Sci. 2017;18:1320. doi: 10.3390/ijms18061320. [DOI] [PMC free article] [PubMed] [Google Scholar]
123.Ho SS, Hung BP, Heyrani N, et al. Hypoxic preconditioning of mesenchymal stem cells with subsequent spheroid formation accelerates repair of segmental bone defects. Stem Cells. 2018;36:1393–1403. doi: 10.1002/stem.2853. [DOI] [PMC free article] [PubMed] [Google Scholar]
124.Lee HJ, Jung YH, Choi GE, et al. O-cyclic phytosphingosine-1-phosphate stimulates HIF1α-dependent glycolytic reprogramming to enhance the therapeutic potential of mesenchymal stem cells. Cell Death Dis. 2019;10:1–21. doi: 10.1038/s41419-019-1823-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
125.Simsek T, Kocabas F, Zheng J, et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell. 2010;7:380–390. doi: 10.1016/j.stem.2010.07.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
126.Hu C, Fan L, Cen P, et al. Energy metabolism plays a critical role in stem cell maintenance and differentiation. Int J Mol Sci. 2016;17:253. doi: 10.3390/ijms17020253. [DOI] [PMC free article] [PubMed] [Google Scholar]
127.Papa L, Djedaini M, Hoffman R. Mitochondrial role in stemness and differentiation of hematopoietic stem cells. Stem Cells Int. 2019;2019:4067162. doi: 10.1155/2019/4067162. [DOI] [PMC free article] [PubMed] [Google Scholar]
128.Ashrafi G, Schwarz TL. The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 2013;20:31–42. doi: 10.1038/cdd.2012.81. [DOI] [PMC free article] [PubMed] [Google Scholar]
129.Davis CO, Kim K-Y, Bushong EA, et al. Transcellular degradation of axonal mitochondria. Proc Natl Acad Sci. 2014;111:9633–9638. doi: 10.1073/pnas.1404651111. [DOI] [PMC free article] [PubMed] [Google Scholar]
130.Wang J, Li H, Yao Y, et al. Stem cell-derived mitochondria transplantation: a novel strategy and the challenges for the treatment of tissue injury. Stem Cell Res Ther. 2018;9:1–10. doi: 10.1186/s13287-018-0832-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
131.Yao Y, Fan X-L, Jiang D, et al. Connexin 43-mediated mitochondrial transfer of iPSC-MSCs alleviates asthma inflammation. Stem Cells Reports. 2018;11:1120–1135. doi: 10.1016/j.stemcr.2018.09.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
132.Boukelmoune N, Chiu GS, Kavelaars A, Heijnen CJ. Mitochondrial transfer from mesenchymal stem cells to neural stem cells protects against the neurotoxic effects of cisplatin. Acta Neuropathol Commun. 2018;6:139. doi: 10.1186/s40478-018-0644-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
133.Zhang Z, Gao Z, Rajthala S, et al. Metabolic reprogramming of normal oral fibroblasts correlated with increased glycolytic metabolism of oral squamous cell carcinoma and precedes their activation into carcinoma associated fibroblasts. Cell Mol Life Sci. 2020;77:1115–1133. doi: 10.1007/s00018-019-03209-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
134.Kim MJ, Hwang JW, Yun C-K, et al. Delivery of exogenous mitochondria via centrifugation enhances cellular metabolic function. Sci Rep. 2018;8:3330. doi: 10.1038/s41598-018-21539-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
135.Cabrera F, Ortega M, Velarde F, et al. Primary allogeneic mitochondrial mix (PAMM) transfer/transplant by MitoCeption to address damage in PBMCs caused by ultraviolet radiation. BMC Biotechnol. 2019;19:42. doi: 10.1186/s12896-019-0534-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
136.Cowan DB, Yao R, Thedsanamoorthy JK, et al. Transit and integration of extracellular mitochondria in human heart cells. Sci Rep. 2017;7:17450. doi: 10.1038/s41598-017-17813-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
137.Levoux J, Prola A, Lafuste P, et al. Platelets facilitate the wound-healing capability of mesenchymal stem cells by mitochondrial transfer and metabolic reprogramming article platelets facilitate the wound-healing capability of mesenchymal stem cells by mitochondrial transfer and met. Cell Metab. 2021;33:1–17. doi: 10.1016/j.cmet.2020.12.006. [DOI] [PubMed] [Google Scholar]
138.Vignais M-L, Caicedo A, Brondello J-M, Jorgensen C. Cell connections by tunneling nanotubes: effects of mitochondrial trafficking on target cell metabolism, homeostasis, and response to therapy. Stem Cells Int. 2017;2017:1–14. doi: 10.1155/2017/6917941. [DOI] [PMC free article] [PubMed] [Google Scholar]
139.Gollihue JL, Rabchevsky AG. Prospects for therapeutic mitochondrial transplantation. Mitochondrion. 2017;35:70–79. doi: 10.1016/j.mito.2017.05.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
140.Sinclair KA, Yerkovich ST, Hopkins PM-A, Chambers DC. Characterization of intercellular communication and mitochondrial donation by mesenchymal stromal cells derived from the human lung. Stem Cell Res Ther. 2016;7:91. doi: 10.1186/s13287-016-0354-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
141.Plotnikov EY, Khryapenkova TG, Galkina SI, et al. Cytoplasm and organelle transfer between mesenchymal multipotent stromal cells and renal tubular cells in co-culture. Exp Cell Res. 2010;316:2447–2455. doi: 10.1016/j.yexcr.2010.06.009. [DOI] [PubMed] [Google Scholar]
142.Torralba D, Baixauli F, Sánchez-Madrid F. Mitochondria know no boundaries: mechanisms and functions of intercellular mitochondrial transfer. Front Cell Dev Biol. 2016;4:107. doi: 10.3389/fcell.2016.00107. [DOI] [PMC free article] [PubMed] [Google Scholar]
143.Grazioli S, Pugin J. Mitochondrial damage-associated molecular patterns: from inflammatory signaling to human diseases. Front Immunol. 2018;9:832. doi: 10.3389/fimmu.2018.00832. [DOI] [PMC free article] [PubMed] [Google Scholar]
144.Tumburu L, Ghosh-choudhary S, Seifuddin FT, et al. Regular article circulating mitochondrial DNA is a proinflammatory DAMP in sickle cell disease. Blood. 2021;137:3116–3126. doi: 10.1182/blood.2020009063. [DOI] [PMC free article] [PubMed] [Google Scholar]
145.Nygren JM, Liuba K, Breitbach M, et al. Myeloid and lymphoid contribution to non-haematopoietic lineages through irradiation-induced heterotypic cell fusion. Nat Cell Biol. 2008;10:584–592. doi: 10.1038/ncb1721. [DOI] [PubMed] [Google Scholar]
146.Wang Y, Branicky R, Noë A, Hekimi S. Superoxide dismutases: Dual roles in controlling ROS damage and regulating ROS signaling. J Cell Biol. 2018;217:1915–1928. doi: 10.1083/jcb.201708007. [DOI] [PMC free article] [PubMed] [Google Scholar]
147.Oh H, Bradfute SB, Gallardo TD, et al. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci USA. 2003;100:12313–12318. doi: 10.1073/pnas.2132126100. [DOI] [PMC free article] [PubMed] [Google Scholar]
148.Golan K, Singh AK, Kollet O, et al. Bone marrow regeneration requires mitochondrial transfer from donor Cx43-expressing hematopoietic progenitors to stroma. Blood. 2020;136:2607–2619. doi: 10.1182/blood.2020005399. [DOI] [PMC free article] [PubMed] [Google Scholar]
149.Dong L-F, Kovarova J, Bajzikova M, et al. Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells. Elife. 2017;6:e22187. doi: 10.7554/eLife.22187. [DOI] [PMC free article] [PubMed] [Google Scholar]
150.Quintero OA, DiVito MM, Adikes RC, et al. Human myo19 is a novel myosin that associates with mitochondria. Curr Biol. 2009;19:2008–2013. doi: 10.1016/j.cub.2009.10.026. [DOI] [PMC free article] [PubMed] [Google Scholar]
151.Brickley K, Stephenson FA. Trafficking kinesin protein (TRAK)-mediated transport of mitochondria in axons of hippocampal neurons. J Biol Chem. 2011;286:18079–18092. doi: 10.1074/jbc.M111.236018. [DOI] [PMC free article] [PubMed] [Google Scholar]
152.Chang KT, Niescier RF, Min K-T. Mitochondrial matrix Ca2+ as an intrinsic signal regulating mitochondrial motility in axons. Proc Natl Acad Sci. 2011;108:15456–15461. doi: 10.1073/pnas.1106862108. [DOI] [PMC free article] [PubMed] [Google Scholar]
153.Hase K, Kimura S, Takatsu H, et al. M-Sec promotes membrane nanotube formation by interacting with Ral and the exocyst complex. Nat Cell Biol. 2009;11:1427–1432. doi: 10.1038/ncb1990. [DOI] [PubMed] [Google Scholar]
154.Hayakawa K, Esposito E, Wang X, et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016;535:551–555. doi: 10.1038/nature18928. [DOI] [PMC free article] [PubMed] [Google Scholar]
155.Marlein CR, Piddock RE, Mistry JJ, et al. CD38-driven mitochondrial trafficking promotes bioenergetic plasticity in multiple myeloma. Cancer Res. 2019;79:2285–2297. doi: 10.1158/0008-5472.CAN-18-0773. [DOI] [PubMed] [Google Scholar]
156.Ikeda G, Santoso MR, Tada Y, et al. Mitochondria-rich extracellular vesicles from autologous stem cell-derived cardiomyocytes restore energetics of ischemic myocardium. J Am Coll Cardiol. 2021;77:1073–1088. doi: 10.1016/j.jacc.2020.12.060. [DOI] [PMC free article] [PubMed] [Google Scholar]
157.Picone P, Porcelli G, Bavisotto CC, et al. Synaptosomes: new vesicles for neuronal mitochondrial transplantation. J Nanobiotechnology. 2021;19:6. doi: 10.1186/s12951-020-00748-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
158.Mobarrez F, Fuzzi E, Gunnarsson I, et al. Microparticles in the blood of patients with SLE: size, content of mitochondria and role in circulating immune complexes. J Autoimmun. 2019;102:142–149. doi: 10.1016/j.jaut.2019.05.003. [DOI] [PubMed] [Google Scholar]
159.Todkar K, Chikhi L, Desjardins V, et al. Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs. Nat Commun. 2021;12:1971. doi: 10.1038/s41467-021-21984-w. [DOI] [PMC free article] [PubMed] [Google Scholar]
160.Levoux J, Prola A, Lafuste P, et al. Article platelets facilitate the wound-healing capability of mesenchymal stem cells by mitochondrial transfer and metabolic reprogramming article platelets facilitate the wound-healing capability of mesenchymal stem cells by mitochondrial transfer and met. Cell Metab. 2021;33:1–17. doi: 10.1016/j.cmet.2020.12.006. [DOI] [PubMed] [Google Scholar]
161.Chou SH, Lan J, Esposito E, et al. Extracellular mitochondria in cerebrospinal fluid and neurological recovery after subarachnoid hemorrhage. Stroke. 2017;48:2231–2237. doi: 10.1161/STROKEAHA.117.017758. [DOI] [PMC free article] [PubMed] [Google Scholar]
162.Dache ZA, Otandault A, Tanos R, et al. Blood contains circulating cell-free respiratory competent mitochondria. Fed Am Soc Exp Biol. 2020;34:1–15. doi: 10.1096/fj.201901917RR. [DOI] [PubMed] [Google Scholar]
163.Stephens OR, Grant D, Frimel M, et al. Characterization and origins of cell-free mitochondria in healthy murine and human blood. Mitochondrion. 2020;54:102–112. doi: 10.1016/j.mito.2020.08.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
164.Song X, Hu W, Yu H, et al. Existence of circulating mitochondria in human and animal peripheral blood. Int J Mol Sci. 2020;21:2122. doi: 10.3390/ijms21062122. [DOI] [PMC free article] [PubMed] [Google Scholar]
165.McCully JD, Emani SM, del Nido PJ. Letter by McCully et al Regarding Article, “Mitochondria Do Not Survive Calcium Overload". Circ Res. 2020;126:e56–e57. doi: 10.1161/CIRCRESAHA.120.316832. [DOI] [PubMed] [Google Scholar]
166.Orfany A, Arriola CG, Doulamis IP, et al. Mitochondrial transplantation ameliorates acute limb ischemia. J Vasc Surg. 2020;71:1014–1026. doi: 10.1016/j.jvs.2019.03.079. [DOI] [PubMed] [Google Scholar]
167.Li X, Zhang Y, Yeung SC, et al. Mitochondrial transfer of induced pluripotent stem cell-derived mesenchymal stem cells to airway epithelial cells attenuates cigarette smoke-induced damage. Am J Respir Cell Mol Biol. 2014;51:455–465. doi: 10.1165/rcmb.2013-0529OC. [DOI] [PubMed] [Google Scholar]
168.de Carvalho LRP, Abreu SC, de Castro LL, et al. Mitochondria-Rich Fraction Isolated From Mesenchymal Stromal Cells Reduces Lung and Distal Organ Injury in Experimental Sepsis. Crit Care Med. 2021;49:e880–e890. doi: 10.1097/CCM.0000000000005056. [DOI] [PubMed] [Google Scholar]
169.Rackham CL, Hubber EL, Czajka A, et al. Optimizing beta cell function through mesenchymal stromal cell-mediated mitochondria transfer. Stem Cells. 2020;38:574–584. doi: 10.1002/stem.3134. [DOI] [PMC free article] [PubMed] [Google Scholar]
170.Konari N, Nagaishi K, Kikuchi S, Fujimiya M. Mitochondria transfer from mesenchymal stem cells structurally and functionally repairs renal proximal tubular epithelial cells in diabetic nephropathy in vivo. Sci Rep. 2019;9:5184. doi: 10.1038/s41598-019-40163-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
171.Gustafsson AB, Gottlieb RA. Heart mitochondria: gates of life and death. Cardiovasc Res. 2007;77:334–343. doi: 10.1093/cvr/cvm005. [DOI] [PubMed] [Google Scholar]
172.Cselenyák A, Pankotai E, Horváth EM, et al. Mesenchymal stem cells rescue cardiomyoblasts from cell death in an in vitro ischemia model via direct cell-to-cell connections. BMC Cell Biol. 2010;11:29. doi: 10.1186/1471-2121-11-29. [DOI] [PMC free article] [PubMed] [Google Scholar]
173.Liu K, Ji K, Guo L, et al. Mesenchymal stem cells rescue injured endothelial cells in an in vitro ischemia–reperfusion model via tunneling nanotube like structure-mediated mitochondrial transfer. Microvasc Res. 2014;92:10–18. doi: 10.1016/j.mvr.2014.01.008. [DOI] [PubMed] [Google Scholar]
174.Han H, Hu J, Yan Q, et al. Bone marrow-derived mesenchymal stem cells rescue injured H9c2 cells via transferring intact mitochondria through tunneling nanotubes in an in vitro simulated ischemia/reperfusion model. Mol Med Rep. 2016;13:1517–1524. doi: 10.3892/mmr.2015.4726. [DOI] [PMC free article] [PubMed] [Google Scholar]
175.Zhang Y, Yu Z, Jiang D, et al. iPSC-MSCs with high intrinsic MIRO1 and sensitivity to TNF-α yield efficacious mitochondrial transfer to rescue anthracycline-induced cardiomyopathy. Stem cell reports. 2016;7:749–763. doi: 10.1016/j.stemcr.2016.08.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
176.Voloboueva LA, Suh SW, Swanson RA, Giffard RG. Inhibition of mitochondrial function in astrocytes: implications for neuroprotection. J Neurochem. 2007;102:1383–1394. doi: 10.1111/j.1471-4159.2007.04634.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
177.Babenko VA, Silachev DN, Zorova LD, et al. Improving the post-stroke therapeutic potency of mesenchymal multipotent stromal cells by cocultivation with cortical neurons: the role of crosstalk between cells. Stem Cells Transl Med. 2015;4:1011–1020. doi: 10.5966/sctm.2015-0010. [DOI] [PMC free article] [PubMed] [Google Scholar]
178.Babenko V, Silachev D, Popkov V, et al. Miro1 enhances mitochondria transfer from multipotent mesenchymal stem cells (MMSC) to neural cells and improves the efficacy of cell recovery. Molecules. 2018;23:687. doi: 10.3390/molecules23030687. [DOI] [PMC free article] [PubMed] [Google Scholar]
179.Alexander JF, Seua AV, Arroyo LD, et al. Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits. Theranostics. 2021;11:3109–3130. doi: 10.7150/thno.53474. [DOI] [PMC free article] [PubMed] [Google Scholar]
180.Jiang D, Gao F, Zhang Y, et al. Mitochondrial transfer of mesenchymal stem cells effectively protects corneal epithelial cells from mitochondrial damage. Cell Death Dis. 2016;7:e2467. doi: 10.1038/cddis.2016.358. [DOI] [PMC free article] [PubMed] [Google Scholar]
181.Ridge SM, Sullivan FJ, Glynn SA. Mesenchymal stem cells: key players in cancer progression. Mol Cancer. 2017;16:31. doi: 10.1186/s12943-017-0597-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
182.Amé-Thomas P, Maby-El Hajjami H, Monvoisin C, et al. Human mesenchymal stem cells isolated from bone marrow and lymphoid organs support tumor B-cell growth: role of stromal cells in follicular lymphoma pathogenesis. Blood. 2007;109:693–702. doi: 10.1182/blood-2006-05-020800. [DOI] [PubMed] [Google Scholar]
183.Kansy BA, Dißmann PA, Hemeda H, et al. The bidirectional tumor - mesenchymal stromal cell interaction promotes the progression of head and neck cancer. Stem Cell Res Ther. 2014;5:95. doi: 10.1186/scrt484. [DOI] [PMC free article] [PubMed] [Google Scholar]
184.Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449:557–563. doi: 10.1038/nature06188. [DOI] [PubMed] [Google Scholar]
185.Prantl L, Muehlberg F, Navone NM, et al. Adipose tissue-derived stem cells promote prostate tumor growth. Prostate. 2010;70:1709–1715. doi: 10.1002/pros.21206. [DOI] [PMC free article] [PubMed] [Google Scholar]
186.Chen Y-C, Gonzalez ME, Burman B, et al. Mesenchymal stem/stromal cell engulfment reveals metastatic advantage in breast cancer. Cell Rep. 2019;27:3916–3926.e5. doi: 10.1016/j.celrep.2019.05.084. [DOI] [PMC free article] [PubMed] [Google Scholar]
187.Krueger TE, Thorek DLJ, Meeker AK, et al. Tumor-infiltrating mesenchymal stem cells: drivers of the immunosuppressive tumor microenvironment in prostate cancer? Prostate. 2019;79:320–330. doi: 10.1002/pros.23738. [DOI] [PMC free article] [PubMed] [Google Scholar]
188.Aponte PM, Caicedo A. Stemness in cancer: stem cells, cancer stem cells, and their microenvironment. Stem Cells Int. 2017;2017:1–17. doi: 10.1155/2017/5619472. [DOI] [PMC free article] [PubMed] [Google Scholar]
189.Marlein CR, Zaitseva L, Piddock RE, et al. NADPH oxidase-2 derived superoxide drives mitochondrial transfer from bone marrow stromal cells to leukemic blasts. Blood. 2017;130:1649–1660. doi: 10.1182/blood-2017-03-772939. [DOI] [PubMed] [Google Scholar]
190.Sundstrøm T, Prestegarden L, Azuaje F, et al. Inhibition of mitochondrial respiration prevents BRAF-mutant melanoma brain metastasis. Acta Neuropathol Commun. 2019;7:55. doi: 10.1186/s40478-019-0712-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
191.Moschoi R, Imbert V, Nebout M, et al. Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy. Blood. 2016;128:253–264. doi: 10.1182/blood-2015-07-655860. [DOI] [PubMed] [Google Scholar]
192.Pasquier J, Guerrouahen BS, Al Thawadi H, et al. Preferential transfer of mitochondria from endothelial to cancer cells through tunneling nanotubes modulates chemoresistance. J Transl Med. 2013;11:94. doi: 10.1186/1479-5876-11-94. [DOI] [PMC free article] [PubMed] [Google Scholar]
193.Caicedo A, Fritz V, Brondello J-M, et al. MitoCeption as a new tool to assess the effects of mesenchymal stem/stromal cell mitochondria on cancer cell metabolism and function. Sci Rep. 2015;5:9073. doi: 10.1038/srep09073. [DOI] [PMC free article] [PubMed] [Google Scholar]
194.Marlein CR, Zaitseva L, Piddock RE, et al. PGC-1α driven mitochondrial biogenesis in stromal cells underpins mitochondrial trafficking to leukemic blasts. Leukemia. 2018;32:2073–2077. doi: 10.1038/s41375-018-0221-y. [DOI] [PubMed] [Google Scholar]
195.Vitale I, Manic G, Coussens LM, et al. Macrophages and metabolism in the tumor microenvironment. Cell Metab. 2019;30:36–50. doi: 10.1016/j.cmet.2019.06.001. [DOI] [PubMed] [Google Scholar]
196.Vyas S, Zaganjor E, Haigis MC. Mitochondria and cancer. Cell. 2016;166:555–566. doi: 10.1016/j.cell.2016.07.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
197.Salem AF, Whitaker-Menezes D, Lin Z, et al. Two-compartment tumor metabolism: Autophagy in the tumor microenvironment and oxidative mitochondrial metabolism (OXPHOS) in cancer cells. Cell Cycle. 2012;11:2545–2559. doi: 10.4161/cc.20920. [DOI] [PMC free article] [PubMed] [Google Scholar]
198.Ertel A, Tsirigos A, Whitaker-Menezes D, et al. Is cancer a metabolic rebellion against host aging? In the quest for immortality, tumor cells try to save themselves by boosting mitochondrial metabolism. Cell Cycle. 2012;11:253–263. doi: 10.4161/cc.11.2.19006. [DOI] [PMC free article] [PubMed] [Google Scholar]
199.Chiavarina B, Martinez-Outschoorn UE, Whitaker-Menezes D, et al. Metabolic reprogramming and two-compartment tumor metabolism. Cell Cycle. 2012;11:3280–3289. doi: 10.4161/cc.21643. [DOI] [PMC free article] [PubMed] [Google Scholar]
200.Guariento A, Doulamis IP, Duignan T, et al. Mitochondrial transplantation for myocardial protection in ex-situ perfused hearts donated after cardio-circulatory death. J Hear Lung Transplant. 2020;39:S87. doi: 10.1016/j.healun.2020.01.1319. [DOI] [PubMed] [Google Scholar]
201.Guariento A, Blitzer D, Doulamis I, et al. Preischemic autologous mitochondrial transplantation by intracoronary injection for myocardial protection. J Thorac Cardiovasc Surg. 2020;160:e15–e29. doi: 10.1016/j.jtcvs.2019.06.111. [DOI] [PubMed] [Google Scholar]
202.McCully JD, Cowan DB, Emani SM, del Nido PJ. Mitochondrial transplantation: from animal models to clinical use in humans. Mitochondrion. 2017;34:127–134. doi: 10.1016/j.mito.2017.03.004. [DOI] [PubMed] [Google Scholar]
203.Wing A, Fajardo CA, Posey AD, et al. Improving CART-cell therapy of solid tumors with oncolytic virus-driven production of a bispecific T-cell engager. Cancer Immunol Res. 2018;6:605–616. doi: 10.1158/2326-6066.CIR-17-0314. [DOI] [PMC free article] [PubMed] [Google Scholar]
204.Patananan AN, Sercel AJ, Wu T, et al. Resource pressure-driven mitochondrial transfer pipeline generates mammalian cells of desired genetic combinations and fates ll pressure-driven mitochondrial transfer pipeline generates mammalian cells of desired genetic combinations and fates. Cell Rep. 2020;33:108562. doi: 10.1016/j.celrep.2020.108562. [DOI] [PMC free article] [PubMed] [Google Scholar]
205.Zhao Y. Stem cell educator therapy and induction of immune balance. Curr Diab Rep. 2012;12:517–523. doi: 10.1007/s11892-012-0308-1. [DOI] [PubMed] [Google Scholar]
206.Emani SM, Piekarski BL, Harrild D, et al. Autologous mitochondrial transplantation for dysfunction after ischemia-reperfusion injury. J Thorac Cardiovasc Surg. 2017;154:286–289. doi: 10.1016/j.jtcvs.2017.02.018. [DOI] [PubMed] [Google Scholar]
207.Roushandeh AM, Kuwahara Y, Roudkenar MH. Mitochondrial transplantation as a potential and novel master key for treatment of various incurable diseases. Cytotechnology. 2019;71:647–663. doi: 10.1007/s10616-019-00302-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
208.Hough KP, Trevor JL, Strenkowski JG, et al. Exosomal transfer of mitochondria from airway myeloid-derived regulatory cells to T cells. Redox Biol. 2018;18:54–64. doi: 10.1016/j.redox.2018.06.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
209.Perico L, Morigi M, Rota C, et al. Human mesenchymal stromal cells transplanted into mice stimulate renal tubular cells and enhance mitochondrial function. Nat Commun. 2017;8:983. doi: 10.1038/s41467-017-00937-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
210.Lin H-C, Liu S-Y, Lai H-S, Lai I-R. Isolated mitochondria infusion mitigates ischemia-reperfusion injury of the liver in rats. Shock. 2013;39:304–310. doi: 10.1097/SHK.0b013e318283035f. [DOI] [PubMed] [Google Scholar]
211.Moskowitzova K, Shin B, Liu K, et al. Mitochondrial transplantation prolongs cold ischemia time in murine heart transplantation. J Heart Lung Transplant. 2019;38:92–99. doi: 10.1016/j.healun.2018.09.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
212.Shin B, Saeed MY, Esch JJ, et al. A novel biological strategy for myocardial protection by intracoronary delivery of mitochondria: safety and efficacy. JAAC. 2019;4:871–888. doi: 10.1016/j.jacbts.2019.08.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
213.Chang J-C, Wu S-L, Liu K-H, et al. Allogeneic/xenogeneic transplantation of peptide-labeled mitochondria in Parkinson’s disease: restoration of mitochondria functions and attenuation of 6-hydroxydopamine–induced neurotoxicity. Transl Res. 2016;170:40–56.e3. doi: 10.1016/j.trsl.2015.12.003. [DOI] [PubMed] [Google Scholar]
214.Chang J-C, Liu K-H, Li Y-C, et al. Functional recovery of human cells harbouring the mitochondrial DNA mutation MERRF A8344G via peptide-mediated mitochondrial delivery. Neurosignals. 2013;21:160–173. doi: 10.1159/000341981. [DOI] [PubMed] [Google Scholar]
215.Gollihue JL, Patel SP, Eldahan KC, et al. Effects of mitochondrial transplantation on bioenergetics, cellular incorporation, and functional recovery after spinal cord injury. J Neurotrauma. 2018;35:1800–1818. doi: 10.1089/neu.2017.5605. [DOI] [PMC free article] [PubMed] [Google Scholar]
216.Fu A, Shi X, Zhang H, Fu B. Mitotherapy for fatty liver by intravenous administration of exogenous mitochondria in male mice. Front Pharmacol. 2017;8:241. doi: 10.3389/fphar.2017.00241. [DOI] [PMC free article] [PubMed] [Google Scholar]
217.Shi X, Bai H, Zhao M, et al. Treatment of acetaminophen-induced liver injury with exogenous mitochondria in mice. Transl Res. 2018;196:31–41. doi: 10.1016/j.trsl.2018.02.003. [DOI] [PubMed] [Google Scholar]
218.Doulamis IP, Guariento A, Duignan T, et al. Mitochondrial transplantation by intra-arterial injection for acute kidney injury. Am J Physiol Physiol. 2020;319:F403–F413. doi: 10.1152/ajprenal.00255.2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
219.Alexander JF, Seua AV, Arroyo LD, et al. Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits. Theranostics. 2021;11:3109. doi: 10.7150/thno.53474. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

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Data Availability Statement

Not applicable.

[CR1] 1.Pittenger MF. Multilineage potential of adult human mesenchymal stem cells. Science (80-) 1999;284:143–147. doi: 10.1126/science.284.5411.143. [DOI] [PubMed] [Google Scholar]

[CR2] 2.Krampera M, Franchini M, Pizzolo G, Aprili G. Mesenchymal stem cells: from biology to clinical use. Blood Transfus. 2007;5:120–129. doi: 10.2450/2007.0029-07. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR3] 3.He A, Jiang Y, Gui C, et al. The antiapoptotic effect of mesenchymal stem cell transplantation on ischemic myocardium is enhanced by anoxic preconditioning. Can J Cardiol. 2009;25:353–358. doi: 10.1016/s0828-282x(09)70094-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR4] 4.Block GJ, Ohkouchi S, Fung F, et al. Multipotent stromal cells are activated to reduce apoptosis in part by upregulation and secretion of stanniocalcin-1. Stem Cells. 2009;27:670–681. doi: 10.1002/stem.20080742. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR5] 5.Weiss ARR, Dahlke MH. Immunomodulation by mesenchymal stem cells (MSCs): mechanisms of action of living, apoptotic, and dead MSCs. Front Immunol. 2019;10:1191. doi: 10.3389/fimmu.2019.01191. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR6] 6.Oh JY, Kim MK, Shin MS, et al. The anti-inflammatory and anti-angiogenic role of mesenchymal stem cells in corneal wound healing following chemical injury. Stem Cells. 2008;26:1047–1055. doi: 10.1634/stemcells.2007-0737. [DOI] [PubMed] [Google Scholar]

[CR7] 7.Zhang R, Liu Y, Yan K, et al. Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury. J Neuroinflammation. 2013;10:871. doi: 10.1186/1742-2094-10-106. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR8] 8.Abdi R, Fiorina P, Adra CN, et al. Immunomodulation by mesenchymal stem cells: a potential therapeutic strategy for type 1 diabetes. Diabetes. 2008;57:1759–1767. doi: 10.2337/db08-0180. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR9] 9.Wang M, Yuan Q, Xie L. Mesenchymal stem cell-based immunomodulation: properties and clinical application. Stem Cells Int. 2018;2018:1–12. doi: 10.1155/2018/3057624. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR10] 10.Wang L-T, Ting C-H, Yen M-L, et al. Human mesenchymal stem cells (MSCs) for treatment towards immune- and inflammation-mediated diseases: review of current clinical trials. J Biomed Sci. 2016;23:76. doi: 10.1186/s12929-016-0289-5. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR11] 11.Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005;105:1815–1822. doi: 10.1182/blood-2004-04-1559. [DOI] [PubMed] [Google Scholar]

[CR12] 12.Kinnaird T, Stabile E, Burnett MS, et al. Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms. Circ Res. 2004;94:678–685. doi: 10.1161/01.RES.0000118601.37875.AC. [DOI] [PubMed] [Google Scholar]

[CR13] 13.Chen J, Li Y, Katakowski M, et al. Intravenous bone marrow stromal cell therapy reduces apoptosis and promotes endogenous cell proliferation after stroke in female rat. J Neurosci Res. 2003;73:778–786. doi: 10.1002/jnr.10691. [DOI] [PubMed] [Google Scholar]

[CR14] 14.Laflamme MA, Murry CE. Regenerating the heart. Nat Biotechnol. 2005;23:845–856. doi: 10.1038/nbt1117. [DOI] [PubMed] [Google Scholar]

[CR15] 15.Murphy JM, Fink DJ, Hunziker EB, Barry FP. Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum. 2003;48:3464–3474. doi: 10.1002/art.11365. [DOI] [PubMed] [Google Scholar]

[CR16] 16.Fellows CR, Matta C, Zakany R, et al. Adipose, bone marrow and synovial joint-derived mesenchymal stem cells for cartilage repair. Front Genet. 2016;7:213. doi: 10.3389/fgene.2016.00213. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR17] 17.Barry F, Murphy M. Mesenchymal stem cells in joint disease and repair. Nat Rev Rheumatol. 2013;9:584–594. doi: 10.1038/nrrheum.2013.109. [DOI] [PubMed] [Google Scholar]

[CR18] 18.Morrison TJ, Jackson MV, Cunningham EK, et al. Mesenchymal stromal cells modulate macrophages in clinically relevant lung injury models by extracellular vesicle mitochondrial transfer. Am J Respir Crit Care Med. 2017;196:1275–1286. doi: 10.1164/rccm.201701-0170OC. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR19] 19.Tisato V, Naresh K, Girdlestone J, et al. Mesenchymal stem cells of cord blood origin are effective at preventing but not treating graft-versus-host disease. Leukemia. 2007;21:1992–1999. doi: 10.1038/sj.leu.2404847. [DOI] [PubMed] [Google Scholar]

[CR20] 20.Wang L, Zhu C, Ma D, et al. Efficacy and safety of mesenchymal stromal cells for the prophylaxis of chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: a meta-analysis of randomized controlled trials. Ann Hematol. 2018;97:1941–1950. doi: 10.1007/s00277-018-3384-8. [DOI] [PubMed] [Google Scholar]

[CR21] 21.Leibacher J, Henschler R. Biodistribution, migration and homing of systemically applied mesenchymal stem/stromal cells. Stem Cell Res Ther. 2016;7:7. doi: 10.1186/s13287-015-0271-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR22] 22.Chen L, Tredget EE, Wu PYG, Wu Y. Paracrine factors of mesenchymal stem cells recruit macrophages and endothelial lineage cells and enhance wound healing. PLoS ONE. 2008;3:e1886. doi: 10.1371/journal.pone.0001886. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR23] 23.Morrison DE, Aitken JB, de Jonge MD, et al. High mitochondrial accumulation of new gadolinium(III) agents within tumour cells. Chem Commun (Camb) 2014;50:2252–2254. doi: 10.1039/c3cc46903d. [DOI] [PubMed] [Google Scholar]

[CR24] 24.Islam MN, Das SR, Emin MT, et al. Mitochondrial transfer from bone-marrow–derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat Med. 2012;18:759–765. doi: 10.1038/nm.2736. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR25] 25.Jackson MV, Morrison TJ, Doherty DF, et al. Mitochondrial transfer via tunneling nanotubes is an important mechanism by which mesenchymal stem cells enhance macrophage phagocytosis in the in vitro and in vivo models of ARDS. Stem Cells. 2016;34:2210–2223. doi: 10.1002/stem.2372. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR26] 26.Acquistapace A, Bru T, Lesault P-F, et al. Human mesenchymal stem cells reprogram adult cardiomyocytes toward a progenitor-like state through partial cell fusion and mitochondria transfer. Stem Cells. 2011;29:812–824. doi: 10.1002/stem.632. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR27] 27.Huda F, Fan Y, Suzuki M, et al. Fusion of human fetal mesenchymal stem cells with “degenerating” cerebellar neurons in spinocerebellar ataxia type 1 model mice. PLoS ONE. 2016;11:e0164202. doi: 10.1371/journal.pone.0164202. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR28] 28.Emani SM, McCully JD. Mitochondrial transplantation: applications for pediatric patients with congenital heart disease. Transl Pediatr. 2018;7:169–175. doi: 10.21037/tp.2018.02.02. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR29] 29.Ramirez-Barbieri G, Moskowitzova K, Shin B, et al. Alloreactivity and allorecognition of syngeneic and allogeneic mitochondria. Mitochondrion. 2019;46:103–115. doi: 10.1016/j.mito.2018.03.002. [DOI] [PubMed] [Google Scholar]

[CR30] 30.Clark MA, Shay JW. Mitochondrial transformation of mammalian cells. Nature. 1982;295:605–607. doi: 10.1038/295605a0. [DOI] [PubMed] [Google Scholar]

[CR31] 31.Rustom A, Saffrich R, Markovic I, et al. Nanotubular highways for intercellular organelle transport. Science (80-) 2004;303:1007–1010. doi: 10.1126/science.1093133. [DOI] [PubMed] [Google Scholar]

[CR32] 32.Gerdes H-H, Bukoreshtliev NV, Barroso JFV. Tunneling nanotubes: a new route for the exchange of components between animal cells. FEBS Lett. 2007;581:2194–2201. doi: 10.1016/j.febslet.2007.03.071. [DOI] [PubMed] [Google Scholar]

[CR33] 33.Miliotis S, Nicolalde B, Ortega M, et al. Forms of extracellular mitochondria and their impact in health. Mitochondrion. 2019;48:16–30. doi: 10.1016/j.mito.2019.02.002. [DOI] [PubMed] [Google Scholar]

[CR34] 34.Caicedo A, Aponte PM, Cabrera F, et al. Artificial mitochondria transfer: current challenges, advances, and future applications. Stem Cells Int. 2017;2017:1–23. doi: 10.1155/2017/7610414. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR35] 35.Spees JL, Olson SD, Whitney MJ, Prockop DJ. Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci USA. 2006;103:1283–1288. doi: 10.1073/pnas.0510511103. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR36] 36.Pittenger MF, Discher DE, Péault BM, et al. Mesenchymal stem cell perspective: cell biology to clinical progress. npj Regen Med. 2019;4:22. doi: 10.1038/s41536-019-0083-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR37] 37.Bartolucci J, Verdugo FJ, González PL, et al. Safety and efficacy of the intravenous infusion of umbilical cord mesenchymal stem cells in patients with heart failure. Circ Res. 2017;121:1192–1204. doi: 10.1161/CIRCRESAHA.117.310712. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR38] 38.Matas J, Orrego M, Amenabar D, et al. Umbilical cord-derived mesenchymal stromal cells (MSCs) for knee osteoarthritis: repeated MSC dosing is superior to a single MSC dose and to hyaluronic acid in a controlled randomized phase I/II trial. Stem Cells Transl Med. 2018;8:215–224. doi: 10.1002/sctm.18-0053. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR39] 39.Caplan H, Olson SD, Kumar A, et al. Mesenchymal stromal cell therapeutic delivery: translational challenges to clinical application. Front Immunol. 2019;10:1645. doi: 10.3389/fimmu.2019.01645. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR40] 40.Couto PS, Shatirishvili G, Bersenev A, Verter F. First decade of clinical trials and published studies with mesenchymal stromal cells from umbilical cord tissue. Regen Med. 2019;14:309–319. doi: 10.2217/rme-2018-0171. [DOI] [PubMed] [Google Scholar]

[CR41] 41.Kurte M, Vega-Letter AM, Luz-Crawford P, et al. Time-dependent LPS exposure commands MSC immunoplasticity through TLR4 activation leading to opposite therapeutic outcome in EAE. Stem Cell Res Ther. 2020;11:416. doi: 10.1186/s13287-020-01840-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR42] 42.Velarde F, Castañeda V, Morales E, et al. Use of human umbilical cord and its byproducts in tissue regeneration. Front Bioeng Biotechnol. 2020;8:117. doi: 10.3389/fbioe.2020.00117. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR43] 43.Fan C-G, Zhang Q, Zhou J. Therapeutic potentials of mesenchymal stem cells derived from human umbilical cord. Stem Cell Rev Reports. 2011;7:195–207. doi: 10.1007/s12015-010-9168-8. [DOI] [PubMed] [Google Scholar]

[CR44] 44.Veryasov VN, Savilova AM, Buyanovskaya OA, et al. Isolation of mesenchymal stromal cells from extraembryonic tissues and their characteristics. Bull Exp Biol Med. 2014;157:119–124. doi: 10.1007/s10517-014-2506-0. [DOI] [PubMed] [Google Scholar]

[CR45] 45.Mabuchi Y, Matsuzaki Y. Prospective isolation of resident adult human mesenchymal stem cell population from multiple organs. Int J Hematol. 2016;103:138–144. doi: 10.1007/s12185-015-1921-y. [DOI] [PubMed] [Google Scholar]

[CR46] 46.Laroye C, Gauthier M, Antonot H, et al. Mesenchymal stem/stromal cell production compliant with good manufacturing practice: comparison between bone marrow, the gold standard adult source, and Wharton’s Jelly, an extraembryonic source. J Clin Med. 2019;8:2207. doi: 10.3390/jcm8122207. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR47] 47.Du WJ, Chi Y, Yang ZX, et al. Heterogeneity of proangiogenic features in mesenchymal stem cells derived from bone marrow, adipose tissue, umbilical cord, and placenta. Stem Cell Res Ther. 2016;7:163. doi: 10.1186/s13287-016-0418-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR48] 48.Ertl J, Pichlsberger M, Tuca A-C, et al. Comparative study of regenerative effects of mesenchymal stem cells derived from placental amnion, chorion and umbilical cord on dermal wounds. Placenta. 2018;65:37–46. doi: 10.1016/j.placenta.2018.04.004. [DOI] [PubMed] [Google Scholar]

[CR49] 49.Wu M, Zhang R, Zou Q, et al. Comparison of the biological characteristics of mesenchymal stem cells derived from the human placenta and umbilical cord. Sci Rep. 2018;8:5014. doi: 10.1038/s41598-018-23396-1. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR50] 50.Deng Y, Zhang Y, Ye L, et al. Umbilical cord-derived mesenchymal stem cells instruct monocytes towards an il10-producing phenotype by secreting IL6 and HGF. Sci Rep. 2016;6:37566. doi: 10.1038/srep37566. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR51] 51.Kern S, Eichler H, Stoeve J, et al. Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells. 2006;24:1294–1301. doi: 10.1634/stemcells.2005-0342. [DOI] [PubMed] [Google Scholar]

[CR52] 52.Mizukami A, Swiech K. Mesenchymal stromal cells: from discovery to manufacturing and commercialization. Stem Cells Int. 2018;2018:1–13. doi: 10.1155/2018/4083921. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR53] 53.Li R, Li X-M, Chen J-R. Clinical efficacy and safety of autologous stem cell transplantation for patients with ST-segment elevation myocardial infarction. Ther Clin Risk Manag. 2016;12:1171–1189. doi: 10.2147/TCRM.S107199. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR54] 54.Murata M, Teshima T. Treatment of steroid-refractory acute graft-versus-host disease using commercial mesenchymal stem cell products. Front Immunol. 2021;12:724380. doi: 10.3389/fimmu.2021.724380. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR55] 55.Gebara N, Rossi A, Skovronova R, et al. Extracellular vesicles, apoptotic bodies and mitochondria: stem cell bioproducts for organ regeneration. Curr Transplant Reports. 2020;7:105–113. doi: 10.1007/s40472-020-00282-2. [DOI] [Google Scholar]

[CR56] 56.Yeo RWY, Lai RC, Zhang B, et al. Mesenchymal stem cell: an efficient mass producer of exosomes for drug delivery. Adv Drug Deliv Rev. 2013;65:336–341. doi: 10.1016/j.addr.2012.07.001. [DOI] [PubMed] [Google Scholar]

[CR57] 57.Mendt M, Rezvani K, Shpall E. Mesenchymal stem cell-derived exosomes for clinical use. Bone Marrow Transplant. 2019;54:789–792. doi: 10.1038/s41409-019-0616-z. [DOI] [PubMed] [Google Scholar]

[CR58] 58.Alcayaga-Miranda F, Varas-Godoy M, Khoury M. Harnessing the angiogenic potential of stem cell-derived exosomes for vascular regeneration. Stem Cells Int. 2016;2016:1–11. doi: 10.1155/2016/3409169. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR59] 59.Squillaro T, Peluso G, Galderisi U. Clinical trials with mesenchymal stem cells: an update. Cell Transplant. 2016;25:829–848. doi: 10.3727/096368915X689622. [DOI] [PubMed] [Google Scholar]

[CR60] 60.Lai RC, Tan SS, Teh BJ, et al. Proteolytic potential of the MSC exosome proteome: implications for an exosome-mediated delivery of therapeutic proteasome. Int J Proteomics. 2012;2012:1–14. doi: 10.1155/2012/971907. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR61] 61.Nassar W, El-Ansary M, Sabry D, et al. Umbilical cord mesenchymal stem cells derived extracellular vesicles can safely ameliorate the progression of chronic kidney diseases. Biomater Res. 2016;20:21. doi: 10.1186/s40824-016-0068-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR62] 62.Yosef OB, Jacoby E, Gruber N, et al. Promising results for kearns-sayre syndrome of first in man treatment by mitochondrial augmentation therapy (457) Neurology. 2020;94:457. [Google Scholar]

[CR63] 63.Almannai M, El-Hattab AW, Ali M, et al. Clinical trials in mitochondrial disorders, an update. Mol Genet Metab. 2020;131:1–13. doi: 10.1016/j.ymgme.2020.10.002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR64] 64.Bottani E, Lamperti C, Prigione A, et al. Therapeutic approaches to treat mitochondrial diseases: “one-size-fits-all” and “precision medicine” strategies. Pharmaceutics. 2020;12:1083. doi: 10.3390/pharmaceutics12111083. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR65] 65.Nicolás-Ávila JA, Lechuga-Vieco AV, Esteban-Martínez L, et al. A network of macrophages supports mitochondrial homeostasis in the heart. Cell. 2020;183:94–109.e23. doi: 10.1016/j.cell.2020.08.031. [DOI] [PubMed] [Google Scholar]

[CR66] 66.Brestoff JR, Wilen CB, Moley JR, et al. Intercellular mitochondria transfer to macrophages regulates white adipose tissue homeostasis and is impaired in obesity. Cell Metab. 2021;33:270–282.e8. doi: 10.1016/j.cmet.2020.11.008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR67] 67.Crewe C, Funcke J-B, Li S, et al. Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes. Cell Metab. 2021;33:1853–1868.e11. doi: 10.1016/j.cmet.2021.08.002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR68] 68.Rodriguez A-M, Nakhle J, Griessinger E, Vignais M-L. Intercellular mitochondria trafficking highlighting the dual role of mesenchymal stem cells as both sensors and rescuers of tissue injury. Cell Cycle. 2018;17:712–721. doi: 10.1080/15384101.2018.1445906. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR69] 69.Li C, Cheung MKH, Han S, et al. Mesenchymal stem cells and their mitochondrial transfer: a double-edged sword. Biosci Rep. 2019;39:BSR20182417. doi: 10.1042/BSR20182417. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR70] 70.Schulze A, Harris AL. How cancer metabolism is tuned for proliferation and vulnerable to disruption. Nature. 2012;491:364–373. doi: 10.1038/nature11706. [DOI] [PubMed] [Google Scholar]

[CR71] 71.Ahmad T, Mukherjee S, Pattnaik B, et al. Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy. EMBO J. 2014;33:994–1010. doi: 10.1002/embj.201386030. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR72] 72.Court AC, Le-Gatt A, Luz-Crawford P, et al. Mitochondrial transfer from MSCs to T cells induces Treg differentiation and restricts inflammatory response. EMBO Rep. 2020;21:e48052. doi: 10.15252/embr.201948052. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR73] 73.Phinney DG, Di Giuseppe M, Njah J, et al. Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs. Nat Commun. 2015;6:8472. doi: 10.1038/ncomms9472. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR74] 74.Puhm F, Afonyushkin T, Resch U, et al. Mitochondria are a subset of extracellular vesicles released by activated monocytes and induce type I IFN and TNF responses in endothelial cells. Circ Res. 2019;125:43–52. doi: 10.1161/CIRCRESAHA.118.314601. [DOI] [PubMed] [Google Scholar]

[CR75] 75.Boudreau LH, Duchez A, Cloutier N, et al. Platelets release mitochondria serving as substrate for bactericidal group IIA-secreted phospholipase A 2 to promote in fl ammation. Blood. 2019;124:2173–2184. doi: 10.1182/blood-2014-05-573543.A.-C.D. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR76] 76.Shi Y, Wang Y, Li Q, et al. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases. Nat Rev Nephrol. 2018;14:493–507. doi: 10.1038/s41581-018-0023-5. [DOI] [PubMed] [Google Scholar]

[CR77] 77.Mistry JJ, Marlein CR, Moore JA, et al. ROS-mediated PI3K activation drives mitochondrial transfer from stromal cells to hematopoietic stem cells in response to infection. Proc Natl Acad Sci USA. 2019;116:24610–24619. doi: 10.1073/pnas.1913278116. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR78] 78.Hofmann AD, Beyer M, Krause-Buchholz U, et al. Oxphos supercomplexes as a hallmark of the mitochondrial phenotype of adipogenic differentiated human MSCS. PLoS ONE. 2012;7:e35160. doi: 10.1371/journal.pone.0035160. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR79] 79.Li Q, Gao Z, Chen Y. The role of mitochondria in osteogenic, adipogenic and chondrogenic differentiation of mesenchymal stem cells. Protein Cell. 2017;8:439–445. doi: 10.1007/s13238-017-0385-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR80] 80.Bertolo A, Capossela S, Fränkl G, et al. Oxidative status predicts quality in human mesenchymal stem cells. Stem Cell Res Ther. 2017;8:1–13. doi: 10.1186/s13287-016-0452-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR81] 81.Wang W, Zhang Y, Lu W, Liu K. Mitochondrial reactive oxygen species regulate adipocyte differentiation of mesenchymal stem cells in hematopoietic stress induced by arabinosylcytosine. PLoS ONE. 2015;10:e0120629. doi: 10.1371/journal.pone.0120629. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR82] 82.Tan J, Xu X, Tong Z, et al. Decreased osteogenesis of adult mesenchymal stem cells by reactive oxygen species under cyclic stretch: a possible mechanism of age related osteoporosis. Bone Res. 2015;3:1–6. doi: 10.1038/boneres.2015.3. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR83] 83.Kanda Y, Hinata T, Kang SW, Watanabe Y. Reactive oxygen species mediate adipocyte differentiation in mesenchymal stem cells. Life Sci. 2011;89:250–258. doi: 10.1016/j.lfs.2011.06.007. [DOI] [PubMed] [Google Scholar]

[CR84] 84.Chen C-T, Shih Y-RV, Kuo TK, et al. Coordinated changes of mitochondrial biogenesis and antioxidant enzymes during osteogenic differentiation of human mesenchymal stem cells. Stem Cells. 2008;26:960–968. doi: 10.1634/stemcells.2007-0509. [DOI] [PubMed] [Google Scholar]

[CR85] 85.Shum LC, White NS, Mills BN, et al. Energy metabolism in mesenchymal. Stem Cells. 2016;25:114–122. doi: 10.1089/scd.2015.0193. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR86] 86.Zhang Y, Marsboom G, Toth PT, Rehman J. Mitochondrial respiration regulates adipogenic differentiation of human mesenchymal stem cells. PLoS ONE. 2013;8:e77077. doi: 10.1371/journal.pone.0077077. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR87] 87.Pattappa G, Heywood HK, de Bruijn JD, Lee DA. The metabolism of human mesenchymal stem cells during proliferation and differentiation. J Cell Physiol. 2011;226:2562–2570. doi: 10.1002/jcp.22605. [DOI] [PubMed] [Google Scholar]

[CR88] 88.Chiu SP, Lee YW, Wu LY, et al. Application of ECIS to assess FCCP-induced changes of MSC micromotion and wound healing migration. Sensors (Switzerland) 2019;19:3210. doi: 10.3390/s19143210. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR89] 89.Mancini OK, Lora M, Cuillerier A, et al. Mitochondrial oxidative stress reduces the immunopotency of mesenchymal stromal cells in adults with coronary artery disease. Circ Res. 2018;122:255–266. doi: 10.1161/CIRCRESAHA.117.311400. [DOI] [PubMed] [Google Scholar]

[CR90] 90.Guo Y, Chi X, Wang Y, et al. Mitochondria transfer enhances proliferation, migration, and osteogenic differentiation of bone marrow mesenchymal stem cell and promotes bone defect healing. Stem Cell Res Ther. 2020;11:245. doi: 10.1186/s13287-020-01704-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR91] 91.Paliwal S, Chaudhuri R, Agrawal A, Mohanty S. Human tissue-specific MSCs demonstrate differential mitochondria transfer abilities that may determine their regenerative abilities. Stem Cell Res Ther. 2018;9:298. doi: 10.1186/s13287-018-1012-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR92] 92.Kitani T, Kami D, Matoba S, Gojo S. Internalization of isolated functional mitochondria: involvement of macropinocytosis. J Cell Mol Med. 2014;18:1694–1703. doi: 10.1111/jcmm.12316. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR93] 93.Zhao Y, Jiang Z, Delgado E, et al. Platelet-derived mitochondria display embryonic stem cell markers and improve pancreatic islet β-cell function in humans. Stem Cells Transl Med. 2017;6:1684–1697. doi: 10.1002/sctm.17-0078. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR94] 94.Duroux-Richard I, Apparailly F, Khoury M. Mitochondrial microRNAs contribute to macrophage immune functions including differentiation, polarization, and activation. Front Physiol. 2021;12:738140. doi: 10.3389/fphys.2021.738140. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR95] 95.Vafai SB, Mootha VK. Mitochondrial disorders as windows into an ancient organelle. Nature. 2012;491:374–383. doi: 10.1038/nature11707. [DOI] [PubMed] [Google Scholar]

[CR96] 96.McBride HM, Neuspiel M, Wasiak S. Mitochondria: more than just a powerhouse. Curr Biol. 2006;16:R551–R560. doi: 10.1016/j.cub.2006.06.054. [DOI] [PubMed] [Google Scholar]

[CR97] 97.Roger AJ, Muñoz-Gómez SA, Kamikawa R. The origin and diversification of mitochondria. Curr Biol. 2017;27:R1177–R1192. doi: 10.1016/j.cub.2017.09.015. [DOI] [PubMed] [Google Scholar]

[CR98] 98.Riley JS, Tait SW. Mitochondrial DNA in inflammation and immunity. EMBO Rep. 2020;21:e49799. doi: 10.15252/embr.201949799. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR99] 99.Tiku V, Tan M-W, Dikic I. Mitochondrial functions in infection and immunity. Trends Cell Biol. 2020;30:263–275. doi: 10.1016/j.tcb.2020.01.006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR100] 100.Peña-Blanco A, García-Sáez AJ. Bax, Bak and beyond—mitochondrial performance in apoptosis. FEBS J. 2018;285:416–431. doi: 10.1111/febs.14186. [DOI] [PubMed] [Google Scholar]

[CR101] 101.Sarasija S, Norman KR. A γ-secretase independent role for presenilin in calcium homeostasis impacts mitochondrial function and morphology in caenorhabditis elegans. Genetics. 2015;201:1453–1466. doi: 10.1534/genetics.115.182808. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR102] 102.Nunnari J, Suomalainen A. Mitochondria: in sickness and in health. Cell. 2012;148:1145–1159. doi: 10.1016/j.cell.2012.02.035. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR103] 103.Tilokani L, Nagashima S, Paupe V, Prudent J. Mitochondrial dynamics: overview of molecular mechanisms. Essays Biochem. 2018;62:341–360. doi: 10.1042/EBC20170104. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR104] 104.Liesa M, Palacín M, Zorzano A. Mitochondrial dynamics in mammalian health and disease. Physiol Rev. 2009;89:799–845. doi: 10.1152/physrev.00030.2008. [DOI] [PubMed] [Google Scholar]

[CR105] 105.Pernas L, Scorrano L. Mito-morphosis: mitochondrial fusion, fission, and cristae remodeling as key mediators of cellular function. Annu Rev Physiol. 2016;78:505–531. doi: 10.1146/annurev-physiol-021115-105011. [DOI] [PubMed] [Google Scholar]

[CR106] 106.Wai T, Langer T. Mitochondrial dynamics and metabolic regulation. Trends Endocrinol Metab. 2016;27:105–117. doi: 10.1016/j.tem.2015.12.001. [DOI] [PubMed] [Google Scholar]

[CR107] 107.Pickles S, Vigié P, Youle RJ. Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol. 2018;28:R170–R185. doi: 10.1016/j.cub.2018.01.004. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR108] 108.Dominy JE, Puigserver P. Mitochondrial biogenesis through activation of nuclear signaling proteins. Cold Spring Harb Perspect Biol. 2013;5:1–16. doi: 10.1101/cshperspect.a015008. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR109] 109.Giacomello M, Pyakurel A, Glytsou C, Scorrano L. The cell biology of mitochondrial dynamics. Nat Rev Mol Cell Biol. 2020;21:204–224. doi: 10.1038/s41580-020-0210-7. [DOI] [PubMed] [Google Scholar]

[CR110] 110.Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr. 2011;93:884S–890S. doi: 10.3945/ajcn.110.001917. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR111] 111.Luo C, Widlund HR, Puigserver P. PGC-1 coactivators: shepherding the mitochondrial biogenesis of tumors. Trends Cancer. 2016;2:619–631. doi: 10.1016/j.trecan.2016.09.006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR112] 112.Scarpulla RC. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta - Mol Cell Res. 2011;1813:1269–1278. doi: 10.1016/j.bbamcr.2010.09.019. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR113] 113.Price NL, Gomes AP, Ling AJY, et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 2012;15:675–690. doi: 10.1016/j.cmet.2012.04.003. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR114] 114.Jin SM, Youle RJ. PINK1-and Parkin-mediated mitophagy at a glance. J Cell Sci. 2012;125:795–799. doi: 10.1242/jcs.093849. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR115] 115.Sato S, Furuya N (2017) Induction of PINK1/Parkin-Mediated Mitophagy. In: Methods in molecular biology. Humana Press Inc., pp 9–17

[CR116] 116.Palikaras K, Lionaki E, Tavernarakis N. Mechanisms of mitophagy in cellular homeostasis, physiology and pathology. Nat Cell Biol. 2018;20:1013–1022. doi: 10.1038/s41556-018-0176-2. [DOI] [PubMed] [Google Scholar]

[CR117] 117.Yoshii SR, Kishi C, Ishihara N, Mizushima N. Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane. J Biol Chem. 2011;286:19630–19640. doi: 10.1074/jbc.M110.209338. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR118] 118.Saito T, Sadoshima J. Molecular mechanisms of mitochondrial autophagy/mitophagy in the heart. Circ Res. 2015;116:1477–1490. doi: 10.1161/CIRCRESAHA.116.303790. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR119] 119.Jorgensen C, Khoury M. Musculoskeletal progenitor/stromal cell-derived mitochondria modulate cell differentiation and therapeutical function. Front Immunol. 2021;12:606781. doi: 10.3389/fimmu.2021.606781. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR120] 120.Fillmore N, Huqi A, Jaswal JS, et al. Effect of fatty acids on human bone marrow mesenchymal stem cell energy metabolism and survival. PLoS ONE. 2015;10:e0120257. doi: 10.1371/journal.pone.0120257. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR121] 121.Shum LC, White NS, Mills BN, et al. Energy metabolism in mesenchymal stem cells during osteogenic differentiation. Stem Cells Dev. 2016;25:114–122. doi: 10.1089/scd.2015.0193. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR122] 122.Lee JH, Yoon YM, Lee SH. Hypoxic preconditioning promotes the bioactivities of mesenchymal stem cells via the HIF-1α-GRP78-Akt axis. Int J Mol Sci. 2017;18:1320. doi: 10.3390/ijms18061320. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR123] 123.Ho SS, Hung BP, Heyrani N, et al. Hypoxic preconditioning of mesenchymal stem cells with subsequent spheroid formation accelerates repair of segmental bone defects. Stem Cells. 2018;36:1393–1403. doi: 10.1002/stem.2853. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR124] 124.Lee HJ, Jung YH, Choi GE, et al. O-cyclic phytosphingosine-1-phosphate stimulates HIF1α-dependent glycolytic reprogramming to enhance the therapeutic potential of mesenchymal stem cells. Cell Death Dis. 2019;10:1–21. doi: 10.1038/s41419-019-1823-7. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR125] 125.Simsek T, Kocabas F, Zheng J, et al. The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell. 2010;7:380–390. doi: 10.1016/j.stem.2010.07.011. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR126] 126.Hu C, Fan L, Cen P, et al. Energy metabolism plays a critical role in stem cell maintenance and differentiation. Int J Mol Sci. 2016;17:253. doi: 10.3390/ijms17020253. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR127] 127.Papa L, Djedaini M, Hoffman R. Mitochondrial role in stemness and differentiation of hematopoietic stem cells. Stem Cells Int. 2019;2019:4067162. doi: 10.1155/2019/4067162. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR128] 128.Ashrafi G, Schwarz TL. The pathways of mitophagy for quality control and clearance of mitochondria. Cell Death Differ. 2013;20:31–42. doi: 10.1038/cdd.2012.81. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR129] 129.Davis CO, Kim K-Y, Bushong EA, et al. Transcellular degradation of axonal mitochondria. Proc Natl Acad Sci. 2014;111:9633–9638. doi: 10.1073/pnas.1404651111. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR130] 130.Wang J, Li H, Yao Y, et al. Stem cell-derived mitochondria transplantation: a novel strategy and the challenges for the treatment of tissue injury. Stem Cell Res Ther. 2018;9:1–10. doi: 10.1186/s13287-018-0832-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR131] 131.Yao Y, Fan X-L, Jiang D, et al. Connexin 43-mediated mitochondrial transfer of iPSC-MSCs alleviates asthma inflammation. Stem Cells Reports. 2018;11:1120–1135. doi: 10.1016/j.stemcr.2018.09.012. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR132] 132.Boukelmoune N, Chiu GS, Kavelaars A, Heijnen CJ. Mitochondrial transfer from mesenchymal stem cells to neural stem cells protects against the neurotoxic effects of cisplatin. Acta Neuropathol Commun. 2018;6:139. doi: 10.1186/s40478-018-0644-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR133] 133.Zhang Z, Gao Z, Rajthala S, et al. Metabolic reprogramming of normal oral fibroblasts correlated with increased glycolytic metabolism of oral squamous cell carcinoma and precedes their activation into carcinoma associated fibroblasts. Cell Mol Life Sci. 2020;77:1115–1133. doi: 10.1007/s00018-019-03209-y. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR134] 134.Kim MJ, Hwang JW, Yun C-K, et al. Delivery of exogenous mitochondria via centrifugation enhances cellular metabolic function. Sci Rep. 2018;8:3330. doi: 10.1038/s41598-018-21539-y. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR135] 135.Cabrera F, Ortega M, Velarde F, et al. Primary allogeneic mitochondrial mix (PAMM) transfer/transplant by MitoCeption to address damage in PBMCs caused by ultraviolet radiation. BMC Biotechnol. 2019;19:42. doi: 10.1186/s12896-019-0534-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR136] 136.Cowan DB, Yao R, Thedsanamoorthy JK, et al. Transit and integration of extracellular mitochondria in human heart cells. Sci Rep. 2017;7:17450. doi: 10.1038/s41598-017-17813-0. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR137] 137.Levoux J, Prola A, Lafuste P, et al. Platelets facilitate the wound-healing capability of mesenchymal stem cells by mitochondrial transfer and metabolic reprogramming article platelets facilitate the wound-healing capability of mesenchymal stem cells by mitochondrial transfer and met. Cell Metab. 2021;33:1–17. doi: 10.1016/j.cmet.2020.12.006. [DOI] [PubMed] [Google Scholar]

[CR138] 138.Vignais M-L, Caicedo A, Brondello J-M, Jorgensen C. Cell connections by tunneling nanotubes: effects of mitochondrial trafficking on target cell metabolism, homeostasis, and response to therapy. Stem Cells Int. 2017;2017:1–14. doi: 10.1155/2017/6917941. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR139] 139.Gollihue JL, Rabchevsky AG. Prospects for therapeutic mitochondrial transplantation. Mitochondrion. 2017;35:70–79. doi: 10.1016/j.mito.2017.05.007. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR140] 140.Sinclair KA, Yerkovich ST, Hopkins PM-A, Chambers DC. Characterization of intercellular communication and mitochondrial donation by mesenchymal stromal cells derived from the human lung. Stem Cell Res Ther. 2016;7:91. doi: 10.1186/s13287-016-0354-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR141] 141.Plotnikov EY, Khryapenkova TG, Galkina SI, et al. Cytoplasm and organelle transfer between mesenchymal multipotent stromal cells and renal tubular cells in co-culture. Exp Cell Res. 2010;316:2447–2455. doi: 10.1016/j.yexcr.2010.06.009. [DOI] [PubMed] [Google Scholar]

[CR142] 142.Torralba D, Baixauli F, Sánchez-Madrid F. Mitochondria know no boundaries: mechanisms and functions of intercellular mitochondrial transfer. Front Cell Dev Biol. 2016;4:107. doi: 10.3389/fcell.2016.00107. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR143] 143.Grazioli S, Pugin J. Mitochondrial damage-associated molecular patterns: from inflammatory signaling to human diseases. Front Immunol. 2018;9:832. doi: 10.3389/fimmu.2018.00832. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR144] 144.Tumburu L, Ghosh-choudhary S, Seifuddin FT, et al. Regular article circulating mitochondrial DNA is a proinflammatory DAMP in sickle cell disease. Blood. 2021;137:3116–3126. doi: 10.1182/blood.2020009063. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR145] 145.Nygren JM, Liuba K, Breitbach M, et al. Myeloid and lymphoid contribution to non-haematopoietic lineages through irradiation-induced heterotypic cell fusion. Nat Cell Biol. 2008;10:584–592. doi: 10.1038/ncb1721. [DOI] [PubMed] [Google Scholar]

[CR146] 146.Wang Y, Branicky R, Noë A, Hekimi S. Superoxide dismutases: Dual roles in controlling ROS damage and regulating ROS signaling. J Cell Biol. 2018;217:1915–1928. doi: 10.1083/jcb.201708007. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR147] 147.Oh H, Bradfute SB, Gallardo TD, et al. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci USA. 2003;100:12313–12318. doi: 10.1073/pnas.2132126100. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR148] 148.Golan K, Singh AK, Kollet O, et al. Bone marrow regeneration requires mitochondrial transfer from donor Cx43-expressing hematopoietic progenitors to stroma. Blood. 2020;136:2607–2619. doi: 10.1182/blood.2020005399. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR149] 149.Dong L-F, Kovarova J, Bajzikova M, et al. Horizontal transfer of whole mitochondria restores tumorigenic potential in mitochondrial DNA-deficient cancer cells. Elife. 2017;6:e22187. doi: 10.7554/eLife.22187. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR150] 150.Quintero OA, DiVito MM, Adikes RC, et al. Human myo19 is a novel myosin that associates with mitochondria. Curr Biol. 2009;19:2008–2013. doi: 10.1016/j.cub.2009.10.026. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR151] 151.Brickley K, Stephenson FA. Trafficking kinesin protein (TRAK)-mediated transport of mitochondria in axons of hippocampal neurons. J Biol Chem. 2011;286:18079–18092. doi: 10.1074/jbc.M111.236018. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR152] 152.Chang KT, Niescier RF, Min K-T. Mitochondrial matrix Ca2+ as an intrinsic signal regulating mitochondrial motility in axons. Proc Natl Acad Sci. 2011;108:15456–15461. doi: 10.1073/pnas.1106862108. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR153] 153.Hase K, Kimura S, Takatsu H, et al. M-Sec promotes membrane nanotube formation by interacting with Ral and the exocyst complex. Nat Cell Biol. 2009;11:1427–1432. doi: 10.1038/ncb1990. [DOI] [PubMed] [Google Scholar]

[CR154] 154.Hayakawa K, Esposito E, Wang X, et al. Transfer of mitochondria from astrocytes to neurons after stroke. Nature. 2016;535:551–555. doi: 10.1038/nature18928. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR155] 155.Marlein CR, Piddock RE, Mistry JJ, et al. CD38-driven mitochondrial trafficking promotes bioenergetic plasticity in multiple myeloma. Cancer Res. 2019;79:2285–2297. doi: 10.1158/0008-5472.CAN-18-0773. [DOI] [PubMed] [Google Scholar]

[CR156] 156.Ikeda G, Santoso MR, Tada Y, et al. Mitochondria-rich extracellular vesicles from autologous stem cell-derived cardiomyocytes restore energetics of ischemic myocardium. J Am Coll Cardiol. 2021;77:1073–1088. doi: 10.1016/j.jacc.2020.12.060. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR157] 157.Picone P, Porcelli G, Bavisotto CC, et al. Synaptosomes: new vesicles for neuronal mitochondrial transplantation. J Nanobiotechnology. 2021;19:6. doi: 10.1186/s12951-020-00748-6. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR158] 158.Mobarrez F, Fuzzi E, Gunnarsson I, et al. Microparticles in the blood of patients with SLE: size, content of mitochondria and role in circulating immune complexes. J Autoimmun. 2019;102:142–149. doi: 10.1016/j.jaut.2019.05.003. [DOI] [PubMed] [Google Scholar]

[CR159] 159.Todkar K, Chikhi L, Desjardins V, et al. Selective packaging of mitochondrial proteins into extracellular vesicles prevents the release of mitochondrial DAMPs. Nat Commun. 2021;12:1971. doi: 10.1038/s41467-021-21984-w. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR160] 160.Levoux J, Prola A, Lafuste P, et al. Article platelets facilitate the wound-healing capability of mesenchymal stem cells by mitochondrial transfer and metabolic reprogramming article platelets facilitate the wound-healing capability of mesenchymal stem cells by mitochondrial transfer and met. Cell Metab. 2021;33:1–17. doi: 10.1016/j.cmet.2020.12.006. [DOI] [PubMed] [Google Scholar]

[CR161] 161.Chou SH, Lan J, Esposito E, et al. Extracellular mitochondria in cerebrospinal fluid and neurological recovery after subarachnoid hemorrhage. Stroke. 2017;48:2231–2237. doi: 10.1161/STROKEAHA.117.017758. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR162] 162.Dache ZA, Otandault A, Tanos R, et al. Blood contains circulating cell-free respiratory competent mitochondria. Fed Am Soc Exp Biol. 2020;34:1–15. doi: 10.1096/fj.201901917RR. [DOI] [PubMed] [Google Scholar]

[CR163] 163.Stephens OR, Grant D, Frimel M, et al. Characterization and origins of cell-free mitochondria in healthy murine and human blood. Mitochondrion. 2020;54:102–112. doi: 10.1016/j.mito.2020.08.002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR164] 164.Song X, Hu W, Yu H, et al. Existence of circulating mitochondria in human and animal peripheral blood. Int J Mol Sci. 2020;21:2122. doi: 10.3390/ijms21062122. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR165] 165.McCully JD, Emani SM, del Nido PJ. Letter by McCully et al Regarding Article, “Mitochondria Do Not Survive Calcium Overload". Circ Res. 2020;126:e56–e57. doi: 10.1161/CIRCRESAHA.120.316832. [DOI] [PubMed] [Google Scholar]

[CR166] 166.Orfany A, Arriola CG, Doulamis IP, et al. Mitochondrial transplantation ameliorates acute limb ischemia. J Vasc Surg. 2020;71:1014–1026. doi: 10.1016/j.jvs.2019.03.079. [DOI] [PubMed] [Google Scholar]

[CR167] 167.Li X, Zhang Y, Yeung SC, et al. Mitochondrial transfer of induced pluripotent stem cell-derived mesenchymal stem cells to airway epithelial cells attenuates cigarette smoke-induced damage. Am J Respir Cell Mol Biol. 2014;51:455–465. doi: 10.1165/rcmb.2013-0529OC. [DOI] [PubMed] [Google Scholar]

[CR168] 168.de Carvalho LRP, Abreu SC, de Castro LL, et al. Mitochondria-Rich Fraction Isolated From Mesenchymal Stromal Cells Reduces Lung and Distal Organ Injury in Experimental Sepsis. Crit Care Med. 2021;49:e880–e890. doi: 10.1097/CCM.0000000000005056. [DOI] [PubMed] [Google Scholar]

[CR169] 169.Rackham CL, Hubber EL, Czajka A, et al. Optimizing beta cell function through mesenchymal stromal cell-mediated mitochondria transfer. Stem Cells. 2020;38:574–584. doi: 10.1002/stem.3134. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR170] 170.Konari N, Nagaishi K, Kikuchi S, Fujimiya M. Mitochondria transfer from mesenchymal stem cells structurally and functionally repairs renal proximal tubular epithelial cells in diabetic nephropathy in vivo. Sci Rep. 2019;9:5184. doi: 10.1038/s41598-019-40163-y. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR171] 171.Gustafsson AB, Gottlieb RA. Heart mitochondria: gates of life and death. Cardiovasc Res. 2007;77:334–343. doi: 10.1093/cvr/cvm005. [DOI] [PubMed] [Google Scholar]

[CR172] 172.Cselenyák A, Pankotai E, Horváth EM, et al. Mesenchymal stem cells rescue cardiomyoblasts from cell death in an in vitro ischemia model via direct cell-to-cell connections. BMC Cell Biol. 2010;11:29. doi: 10.1186/1471-2121-11-29. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR173] 173.Liu K, Ji K, Guo L, et al. Mesenchymal stem cells rescue injured endothelial cells in an in vitro ischemia–reperfusion model via tunneling nanotube like structure-mediated mitochondrial transfer. Microvasc Res. 2014;92:10–18. doi: 10.1016/j.mvr.2014.01.008. [DOI] [PubMed] [Google Scholar]

[CR174] 174.Han H, Hu J, Yan Q, et al. Bone marrow-derived mesenchymal stem cells rescue injured H9c2 cells via transferring intact mitochondria through tunneling nanotubes in an in vitro simulated ischemia/reperfusion model. Mol Med Rep. 2016;13:1517–1524. doi: 10.3892/mmr.2015.4726. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR175] 175.Zhang Y, Yu Z, Jiang D, et al. iPSC-MSCs with high intrinsic MIRO1 and sensitivity to TNF-α yield efficacious mitochondrial transfer to rescue anthracycline-induced cardiomyopathy. Stem cell reports. 2016;7:749–763. doi: 10.1016/j.stemcr.2016.08.009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR176] 176.Voloboueva LA, Suh SW, Swanson RA, Giffard RG. Inhibition of mitochondrial function in astrocytes: implications for neuroprotection. J Neurochem. 2007;102:1383–1394. doi: 10.1111/j.1471-4159.2007.04634.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR177] 177.Babenko VA, Silachev DN, Zorova LD, et al. Improving the post-stroke therapeutic potency of mesenchymal multipotent stromal cells by cocultivation with cortical neurons: the role of crosstalk between cells. Stem Cells Transl Med. 2015;4:1011–1020. doi: 10.5966/sctm.2015-0010. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR178] 178.Babenko V, Silachev D, Popkov V, et al. Miro1 enhances mitochondria transfer from multipotent mesenchymal stem cells (MMSC) to neural cells and improves the efficacy of cell recovery. Molecules. 2018;23:687. doi: 10.3390/molecules23030687. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR179] 179.Alexander JF, Seua AV, Arroyo LD, et al. Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits. Theranostics. 2021;11:3109–3130. doi: 10.7150/thno.53474. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR180] 180.Jiang D, Gao F, Zhang Y, et al. Mitochondrial transfer of mesenchymal stem cells effectively protects corneal epithelial cells from mitochondrial damage. Cell Death Dis. 2016;7:e2467. doi: 10.1038/cddis.2016.358. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR181] 181.Ridge SM, Sullivan FJ, Glynn SA. Mesenchymal stem cells: key players in cancer progression. Mol Cancer. 2017;16:31. doi: 10.1186/s12943-017-0597-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR182] 182.Amé-Thomas P, Maby-El Hajjami H, Monvoisin C, et al. Human mesenchymal stem cells isolated from bone marrow and lymphoid organs support tumor B-cell growth: role of stromal cells in follicular lymphoma pathogenesis. Blood. 2007;109:693–702. doi: 10.1182/blood-2006-05-020800. [DOI] [PubMed] [Google Scholar]

[CR183] 183.Kansy BA, Dißmann PA, Hemeda H, et al. The bidirectional tumor - mesenchymal stromal cell interaction promotes the progression of head and neck cancer. Stem Cell Res Ther. 2014;5:95. doi: 10.1186/scrt484. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR184] 184.Karnoub AE, Dash AB, Vo AP, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449:557–563. doi: 10.1038/nature06188. [DOI] [PubMed] [Google Scholar]

[CR185] 185.Prantl L, Muehlberg F, Navone NM, et al. Adipose tissue-derived stem cells promote prostate tumor growth. Prostate. 2010;70:1709–1715. doi: 10.1002/pros.21206. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR186] 186.Chen Y-C, Gonzalez ME, Burman B, et al. Mesenchymal stem/stromal cell engulfment reveals metastatic advantage in breast cancer. Cell Rep. 2019;27:3916–3926.e5. doi: 10.1016/j.celrep.2019.05.084. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR187] 187.Krueger TE, Thorek DLJ, Meeker AK, et al. Tumor-infiltrating mesenchymal stem cells: drivers of the immunosuppressive tumor microenvironment in prostate cancer? Prostate. 2019;79:320–330. doi: 10.1002/pros.23738. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR188] 188.Aponte PM, Caicedo A. Stemness in cancer: stem cells, cancer stem cells, and their microenvironment. Stem Cells Int. 2017;2017:1–17. doi: 10.1155/2017/5619472. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR189] 189.Marlein CR, Zaitseva L, Piddock RE, et al. NADPH oxidase-2 derived superoxide drives mitochondrial transfer from bone marrow stromal cells to leukemic blasts. Blood. 2017;130:1649–1660. doi: 10.1182/blood-2017-03-772939. [DOI] [PubMed] [Google Scholar]

[CR190] 190.Sundstrøm T, Prestegarden L, Azuaje F, et al. Inhibition of mitochondrial respiration prevents BRAF-mutant melanoma brain metastasis. Acta Neuropathol Commun. 2019;7:55. doi: 10.1186/s40478-019-0712-8. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR191] 191.Moschoi R, Imbert V, Nebout M, et al. Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy. Blood. 2016;128:253–264. doi: 10.1182/blood-2015-07-655860. [DOI] [PubMed] [Google Scholar]

[CR192] 192.Pasquier J, Guerrouahen BS, Al Thawadi H, et al. Preferential transfer of mitochondria from endothelial to cancer cells through tunneling nanotubes modulates chemoresistance. J Transl Med. 2013;11:94. doi: 10.1186/1479-5876-11-94. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR193] 193.Caicedo A, Fritz V, Brondello J-M, et al. MitoCeption as a new tool to assess the effects of mesenchymal stem/stromal cell mitochondria on cancer cell metabolism and function. Sci Rep. 2015;5:9073. doi: 10.1038/srep09073. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR194] 194.Marlein CR, Zaitseva L, Piddock RE, et al. PGC-1α driven mitochondrial biogenesis in stromal cells underpins mitochondrial trafficking to leukemic blasts. Leukemia. 2018;32:2073–2077. doi: 10.1038/s41375-018-0221-y. [DOI] [PubMed] [Google Scholar]

[CR195] 195.Vitale I, Manic G, Coussens LM, et al. Macrophages and metabolism in the tumor microenvironment. Cell Metab. 2019;30:36–50. doi: 10.1016/j.cmet.2019.06.001. [DOI] [PubMed] [Google Scholar]

[CR196] 196.Vyas S, Zaganjor E, Haigis MC. Mitochondria and cancer. Cell. 2016;166:555–566. doi: 10.1016/j.cell.2016.07.002. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR197] 197.Salem AF, Whitaker-Menezes D, Lin Z, et al. Two-compartment tumor metabolism: Autophagy in the tumor microenvironment and oxidative mitochondrial metabolism (OXPHOS) in cancer cells. Cell Cycle. 2012;11:2545–2559. doi: 10.4161/cc.20920. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR198] 198.Ertel A, Tsirigos A, Whitaker-Menezes D, et al. Is cancer a metabolic rebellion against host aging? In the quest for immortality, tumor cells try to save themselves by boosting mitochondrial metabolism. Cell Cycle. 2012;11:253–263. doi: 10.4161/cc.11.2.19006. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR199] 199.Chiavarina B, Martinez-Outschoorn UE, Whitaker-Menezes D, et al. Metabolic reprogramming and two-compartment tumor metabolism. Cell Cycle. 2012;11:3280–3289. doi: 10.4161/cc.21643. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR200] 200.Guariento A, Doulamis IP, Duignan T, et al. Mitochondrial transplantation for myocardial protection in ex-situ perfused hearts donated after cardio-circulatory death. J Hear Lung Transplant. 2020;39:S87. doi: 10.1016/j.healun.2020.01.1319. [DOI] [PubMed] [Google Scholar]

[CR201] 201.Guariento A, Blitzer D, Doulamis I, et al. Preischemic autologous mitochondrial transplantation by intracoronary injection for myocardial protection. J Thorac Cardiovasc Surg. 2020;160:e15–e29. doi: 10.1016/j.jtcvs.2019.06.111. [DOI] [PubMed] [Google Scholar]

[CR202] 202.McCully JD, Cowan DB, Emani SM, del Nido PJ. Mitochondrial transplantation: from animal models to clinical use in humans. Mitochondrion. 2017;34:127–134. doi: 10.1016/j.mito.2017.03.004. [DOI] [PubMed] [Google Scholar]

[CR203] 203.Wing A, Fajardo CA, Posey AD, et al. Improving CART-cell therapy of solid tumors with oncolytic virus-driven production of a bispecific T-cell engager. Cancer Immunol Res. 2018;6:605–616. doi: 10.1158/2326-6066.CIR-17-0314. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR204] 204.Patananan AN, Sercel AJ, Wu T, et al. Resource pressure-driven mitochondrial transfer pipeline generates mammalian cells of desired genetic combinations and fates ll pressure-driven mitochondrial transfer pipeline generates mammalian cells of desired genetic combinations and fates. Cell Rep. 2020;33:108562. doi: 10.1016/j.celrep.2020.108562. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR205] 205.Zhao Y. Stem cell educator therapy and induction of immune balance. Curr Diab Rep. 2012;12:517–523. doi: 10.1007/s11892-012-0308-1. [DOI] [PubMed] [Google Scholar]

[CR206] 206.Emani SM, Piekarski BL, Harrild D, et al. Autologous mitochondrial transplantation for dysfunction after ischemia-reperfusion injury. J Thorac Cardiovasc Surg. 2017;154:286–289. doi: 10.1016/j.jtcvs.2017.02.018. [DOI] [PubMed] [Google Scholar]

[CR207] 207.Roushandeh AM, Kuwahara Y, Roudkenar MH. Mitochondrial transplantation as a potential and novel master key for treatment of various incurable diseases. Cytotechnology. 2019;71:647–663. doi: 10.1007/s10616-019-00302-9. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR208] 208.Hough KP, Trevor JL, Strenkowski JG, et al. Exosomal transfer of mitochondria from airway myeloid-derived regulatory cells to T cells. Redox Biol. 2018;18:54–64. doi: 10.1016/j.redox.2018.06.009. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR209] 209.Perico L, Morigi M, Rota C, et al. Human mesenchymal stromal cells transplanted into mice stimulate renal tubular cells and enhance mitochondrial function. Nat Commun. 2017;8:983. doi: 10.1038/s41467-017-00937-2. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR210] 210.Lin H-C, Liu S-Y, Lai H-S, Lai I-R. Isolated mitochondria infusion mitigates ischemia-reperfusion injury of the liver in rats. Shock. 2013;39:304–310. doi: 10.1097/SHK.0b013e318283035f. [DOI] [PubMed] [Google Scholar]

[CR211] 211.Moskowitzova K, Shin B, Liu K, et al. Mitochondrial transplantation prolongs cold ischemia time in murine heart transplantation. J Heart Lung Transplant. 2019;38:92–99. doi: 10.1016/j.healun.2018.09.025. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR212] 212.Shin B, Saeed MY, Esch JJ, et al. A novel biological strategy for myocardial protection by intracoronary delivery of mitochondria: safety and efficacy. JAAC. 2019;4:871–888. doi: 10.1016/j.jacbts.2019.08.007. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR213] 213.Chang J-C, Wu S-L, Liu K-H, et al. Allogeneic/xenogeneic transplantation of peptide-labeled mitochondria in Parkinson’s disease: restoration of mitochondria functions and attenuation of 6-hydroxydopamine–induced neurotoxicity. Transl Res. 2016;170:40–56.e3. doi: 10.1016/j.trsl.2015.12.003. [DOI] [PubMed] [Google Scholar]

[CR214] 214.Chang J-C, Liu K-H, Li Y-C, et al. Functional recovery of human cells harbouring the mitochondrial DNA mutation MERRF A8344G via peptide-mediated mitochondrial delivery. Neurosignals. 2013;21:160–173. doi: 10.1159/000341981. [DOI] [PubMed] [Google Scholar]

[CR215] 215.Gollihue JL, Patel SP, Eldahan KC, et al. Effects of mitochondrial transplantation on bioenergetics, cellular incorporation, and functional recovery after spinal cord injury. J Neurotrauma. 2018;35:1800–1818. doi: 10.1089/neu.2017.5605. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR216] 216.Fu A, Shi X, Zhang H, Fu B. Mitotherapy for fatty liver by intravenous administration of exogenous mitochondria in male mice. Front Pharmacol. 2017;8:241. doi: 10.3389/fphar.2017.00241. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR217] 217.Shi X, Bai H, Zhao M, et al. Treatment of acetaminophen-induced liver injury with exogenous mitochondria in mice. Transl Res. 2018;196:31–41. doi: 10.1016/j.trsl.2018.02.003. [DOI] [PubMed] [Google Scholar]

[CR218] 218.Doulamis IP, Guariento A, Duignan T, et al. Mitochondrial transplantation by intra-arterial injection for acute kidney injury. Am J Physiol Physiol. 2020;319:F403–F413. doi: 10.1152/ajprenal.00255.2020. [DOI] [PMC free article] [PubMed] [Google Scholar]

[CR219] 219.Alexander JF, Seua AV, Arroyo LD, et al. Nasal administration of mitochondria reverses chemotherapy-induced cognitive deficits. Theranostics. 2021;11:3109. doi: 10.7150/thno.53474. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Mesenchymal stem cell-mediated transfer of mitochondria: mechanisms and functional impact

Francesca Velarde

Sarah Ezquerra

Xavier Delbruyere

Andres Caicedo

Yessia Hidalgo

Maroun Khoury

Abstract

High road for MSCs’ translational avenues

Fig. 1.

Mesenchymal stem/stromal: a frontliner in cell therapy

Fig. 2.

Mitochondrial transfer: more than just energy transfer

MSCs-derived mitochondria, what makes them special

Mitochondria motivated by dynamic purposes

Metabolic changes: a trigger for mitochondrial dynamics

Internalization of exogenous mitochondria

Mitochondria responding the emergency call

Mitochondria transfer within the niche

Fig. 3.

Mitochondria computing the tunneling nanotubes network

Alternative routes for mitochondria transfer

Mitochondria in vesicles: a safer way to travel?

Fig. 4.

Table 1.

Lung diseases and tissue repair

Improving macrophage response

Regulating insulin release

Saving cardiac tissue

Neuronal protection

The other side of mitochondria transfer: an increased malignancy in cancer cells

Limitations and future perspectives

Final remarks

Author contributions

Funding

Data availability

Code availability

Declarations

Conflict of interest

Ethical approval

Consent to participate

Consent for publication

Footnotes

Contributor Information

References

Associated Data

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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