Abstract
Studies of mesenchymal stem (or stromal) cells (MSCs) have moved from bedside to bench and back again. The stromal cells or fibroblasts are found in all tissues and participate in building the extracellular matrix (ECM). Bone marrow (BM)-derived MSCs have been studied for more than 50 years and have multiple roles. They function as stem cells and give rise to bone, cartilage, and fat in the BM (these are stem cells); support hematopoiesis (pericytes); and participate in sensing environmental changes and balancing pro- and anti-inflammatory conditions. In disease states, they migrate to sites of injury and release cytokines, hormones, nucleic acids depending on the microenvironment they find. Clinicians have begun to exploit these properties of BM, adipose tissue, and umbilical cord MSCs because they are easy to harvest and expand in culture. In this review, I describe the uses to which MSCs have been put, list ongoing clinical trials by organ system, and outline how MSCs are thought to regulate the innate and adaptive immune systems. I will discuss some of the reasons why clinical applications are still lacking. Much more work will have to be done to find the sources, doses, and culture conditions needed to exploit MSCs optimally and learn their healing potential. They are worth the effort.
Graphical Abstract
Graphical Abstract.
Significance Statement.
After bone marrow derived stromal cells (MSCs) were used to to treat GVHD in a child in 2004, many additional basic and clinical studies of the cells were published. Two decades of work resulted in hundreds of clinical trials but there is still no consensus about the diseases that should be targeted, the types and doses of cells to use, the best way to administer them, and the frequency with which they should be given. It is clear that MSCs cause no harmful side effects and they do have unique properties. The most interesting feature of the cells is that they adapt to their surroundings, reprogramming cells like macrophages when they are causing harm. Once we figure out the right way to take advantage of this, we will have a powerful approach to treat a number of diseases. This review lists ongoing trials, grouping them by organ system, and it discusses the reasons MSC research has moved more slowly than one hoped it might.
Introduction
Bone marrow stromal cells (BMSCs; or mesenchymal stem or stromal cells, also called MSCs which is the name I will use in this review) were discovered and first studied in detail by Friedenstein et al .1 They found that there are cells in the bone marrow that could differentiate into the various mature cells found there and suggested that the marrow space is a unique environment where stem cells might respond to local needs. When MSCs are placed in another site, the bone might form with or without hematopoiesis: “The results obtained show that differentiation of the stem cells toward osteogenesis requires cell interaction within the cell community at a certain crucial moment”.1 The bone marrow stroma was thought to be a building block of the bone marrow (BM) environment for many decades producing matrix proteins typical for the BM environment. The heterogeneous population of bone marrow MSCs containing multipotent progenitors is defined by their quick adherence to plastic and the ability to form colonies. In addition, according to the definition by the International Society for Cellular Therapy, they must express CD105, CD73, and CD90 and must be negative for CD45, CD34, CD14, CD11b, CD79a, CD19, and HLA-DR surface molecules.2 They differentiate into 3 lineages—bone, cartilage, and fat cells. Lazarus suggested that restoring the BM micro-environment using in vivo expansion and co-transfusion of BMSCs with HSCs improved BM reconstitution with hematopoietic cells and showed that infusion of in vitro expanded MSCs was safe in all doses used.3 DiNicola and coworkers suggested that MSCs may also suppress induced T-cell proliferation, a result of their production of soluble factors.4 This finding suggested that they might be used to mitigate graft versus host disease (GVHD) following bone marrow transplantation. The idea was especially attractive because there appeared to be no rejection of MSCs even if the cells were allogeneic and not autologous in origin.5 This feature was thought to be based on the lack of expression of co-stimulatory molecules or HLA type II antigen.6 Given this, Katarina LeBlanc’s group used MSC therapy to treat a patient with severe GVHD after all other treatments had failed. After they transplanted haploidentical MSCs they found that the “clinical response was striking”. They published their paper 1 year after the MSC treatment and the patient was doing well at the time.7 Similarly, a year later another study of Lazarus showed that co-transplantation of MSCs and HSCs improved the occurrence and reduced severity of GVHD in cancer patients after myeloablation and BM transplantation.8 This result gave rise to a new and exciting field. Members of many other groups began to look for effects of MSCs hoping to drive inflammatory disorders back to normal, no matter how far or in which direction they had veered out of the normal range. Many reviews of this work have been published and I cannot summarize them all. My colleagues and I have reviewed studies of MSCs in infectious diseases and summarized the interactions between the MSCs and a variety of cells of the immune system.9 In this paper, I have focused on human MSCs in vitro and ongoing clinical trials. In the Discussion section, I have tried to summarize what is known about the potential mechanisms of actions responsible for immune modulation by MSCs and the questions that we need to answer before we can use the cells optimally.10 Unless specified differently, MSC below refers to cells derived from bone marrow. Due to the vast amount of data in the literature, I will not attempt to list all clinical trials that have been done or planned to date. An extensive list of these can be found in recent reviews.11,12
GVHD
As I mentioned in the Introduction, the first clinical use of systemic human MSCs was in acute GVHD (aGVHD) following bone marrow transplantation in a child.7 After that study was done, many others established that MSC therapy in acute GVHD is safe, and some showed efficacy. Since the leading cause of death after allogeneic hematopoietic stem cell (HSC) transplantation is a GVHD-induced organ failure, novel treatments are needed. Thus, even though our understanding of their mechanisms of action is incomplete, interest in using MSCs or MSC products to fight steroid-resistant aGVHD has remained high. Steroid therapy is thought to fail in about half of pediatric patients following BM transplant. MSCs have been tested in many trials all over the world as a second line of treatments.13 A review of these trials has appeared recently. Among 25 patients, 24% had complete remissions and 76% had partial responses. None of the patients who had complete remissions died; 26% of the patients who had partial remissions died. In a summary of 92 refractory GVHD patients in several countries (including pediatric as well as adult patients) MSC infusions (both BM- and umbilical cord (UC)-derived cells) were found safe and efficacious.14,15 Ninety-six percent of the steroid-refractory patients responded to the treatments; 72% had complete responses.
The patients in the studies described above received MSC-Frankfurt am Main (MSC–FFM)16 preparations which are manufactured by pooling mononuclear cells from 8 patients’ bone marrow aspirates. Aliquots of the pooled samples are passaged twice after they are thawed and prepared for administration. The concept behind pooling different donor-derived MSCs is to even out donor variations since there is no good marker to select the donor MSCs that perform best in patients.
At present, there are 40 registered clinical trials testing the efficacy of BM-, UC-, and adipose-derived (ADSC) MSCs (Table 1). The primary goal of MSC therapy in GVHD is the suppression of the T-cell response to the host organs after the graft takes hold. There are a few suggested mechanisms underlying the T-cell suppressive behavior of MSCs (see17). In their original report of MSCs’ ability to suppress T-cell proliferation, DiNicola et al suggested that soluble hepatocyte growth factor (HGF) and transforming growth factor-beta (TGF-β) contribute to the development of GVHD.4 In humans, it is generally accepted now that IL-10 and indolamine 2,3 dioxygenase (IDO) are among the several mediators of the immune-suppressive behavior of MSCs. MSCs were shown to make IDO protein and they exhibit increased IDO activity upon stimulation with IFN-γ.18
Table 1.
Graft versus host disease (GVHD).
Monocyte-induced activation appears to be necessary for the MSCs to achieve T-cell suppression and IL1-β may mediate this effect through downregulation of T-cell activation factors.19 Rasmusson et al have reported that IL2, IL10, and possibly prostaglandins may contribute to immune suppression by human MSCs.20 Sato’s group described the role of MSC-derived nitric oxide in mediating T-cell suppression,21 a finding later confirmed by Ren et al22 who added that when MSCs are stimulated by interferon-gamma and an additional pro-inflammatory cytokine (such as TNFα, IL1α, or β) they will produce NO and chemokines that attract T cells bearing the appropriate chemokine receptors. Once the T cells are attracted to the MSCs, MSC-derived NO inhibits their further proliferation. Both Sato and Ren worked with mouse MSCs, and they used knockout animals in their work.
Over time, additional factors have come to light that contribute to the MSC-driven inhibition of T-cell proliferation. Jones et al demonstrated that human MSCs arrest T cells in the G0/G1 cell cycle and decrease their pro-inflammatory environment.23 MSC-derived Galectin-1 (a cell/cell contact modulator) and Sema-3A (a chemo-repellant) were later found to bind to neuropilin 1 (NRP-1).24 Neuropilin-1 is constitutively expressed on the surface of T cells and when it binds to semaphorin, the cells arrest in G0/G1 cell cycle, which was the mechanism suggested also by Jones.23 Another important discovery in mice was described by Choi in 2011, who added another soluble factor to the known and ever-broadening arsenal of MSCs immune suppressive factors, TNF alpha-induced protein 6 (TSG6 or TNFAIP6). TSG6 is a secretory protein that downregulates NF-κB signaling25 and thus decreases cell proliferation. In addition, it was also demonstrated that cell to cell contact with pro-inflammatory macrophages induces TSG6 production and results in more efficient suppression of CD4 T-cell proliferation26 in mice.
Airway and Lung Diseases Including COVID-19 Induced ARDS (Acute Respiratory Distress Syndrome)
One of the first studies using human MSCs in Escherichia coli induced pneumonia in the mouse suggested that MSCs possessed intrinsic antibacterial properties. When the MSCs were applied to the tracheae of sick mice they significantly reduced bacterial growth due to their production and secretion of cathelicidin LL-37.27 Preclinical animal models of a variety of lung diseases were reviewed by Cruz and Rocco recently.28
One of the first clinical studies of MSCs in lung disease (NCT00683722) was done in patients with COPD. There was no significant difference in the adverse events in treated (IV infusion of allogeneic MSC once a month for 4 months) versus placebo groups. There was also no significant difference between the 2 groups after 2 years on COPD progression or quality of life. However, in patients who entered the trial with elevated C reactive protein (CRP) levels, a significant decrease in CRP was observed following MSC administration.29
A single-center phase Ib trial was initiated with placenta-derived human MSCs in patients with idiopathic pulmonary fibrosis (IPF). IPF is thought to be due to failed epithelial repair following injuries to the alveolar type II epithelial cells resulting in the over-proliferation of fibroblasts and deposition of collagen.30 As in the COPD trial, the treatment was safe, but no improvement (and no progression) was observed with the doses used in the study.31 In another phase Ib trial, endobronchial infusions of adipose-derived MSCs were given to IPF patients. The MSCs seemed safe, but efficacy was not demonstrated.32
A phase I, dose-escalation study was performed in patients with bronchopulmonary dysplasia or BPD, a chronic lung disease was seen in preterm infants. Umbilical cord MSCs were administered. The treatment proved safe and a significant reduction in inflammatory markers in tracheal aspirates was observed.33 Several trials are being conducted to explore the therapeutic benefit of MSCs in BPD (see34).
Sarcoidosis, a complex autoimmune disorder, frequently presents in the lung and causes airway inflammation and decline in pulmonary function. The disease is treated with steroids which are harmful in the long run. In a recent study, mononuclear cells (70%–95% macrophages) were freshly isolated from bronchoalveolar lavage fluid of sarcoidosis patients and cocultured with allogeneic MSCs from healthy donors. There was a statistically significant decrease in pro-inflammatory TNFα production by the airway macrophages and a significant increase in their production and release of IL-10, an anti-inflammatory cytokine. The authors suggested that MSC treatment in such patients might alleviate their symptoms and decrease their need for steroids.35
When the COVID-19 epidemic started it soon became evident that the virus targets the lungs and can quickly lead to severe pneumonia, ARDS, organ failure, and death. The use of MSC therapy was considered.36 In an earlier study (NCT01775774) 2 different doses of cells were given to ARDS patients found to be safe.37 Cocultures of BMSCs and broncho-alveolar lavage (BAL) derived cells from patients with ARDS confirmed that MSCs respond to the actual inflammatory environment in a disease-specific manner.38 In a phase I clinical trial, UC and placental MSCs were administered intravenously to COVID-19 patients. No serious adverse effects were reported and a reduced dyspnea and a significant decrease of pro-inflammatory biomarkers in the serum of 7 out of 11 patients were found. Patients who developed sepsis before the infusions did not seem to respond to treatment.39 There are over 50 ongoing clinical trials to test various sources and doses of MSCs in COVID patients with ARD. Lists of these trials and summaries of available findings are available in recent reviews.12,40 Since the beginning of MSC research it has been assumed that most intravenously administered MSCs are trapped in lung capillaries. Thus, it was logical to think of the variety of ways they could help fight COVID-19 disease progression. Many studies have shown that the inflammatory cytokine environment will induce the immune-suppressive behavior of MSCs. An excellent recent review41 gives a good overview of possible responses of MSCs to INFγ stimulation in the pro-inflammatory environment associated with viral infections (eg, COVID-19) of the lungs. These MSC effects are thought to be due to released anti-inflammatory cytokines that can “tame” the proinflammatory cells in the vicinity of the MSCs. Also, in addition to immune regulation, they have been known to help in tissue repair in cellular regeneration. Thus, ideally, when the timing and the dosing are right the MSCs could help to block disease progression and/or to help and speed up healing of COVID-1 9-induced lung disease at several levels. A summary of ongoing clinical trials for lung diseases is listed in Table 2.
Table 2.
Respiratory system/COVID-19- related diseases.
Skeletal Diseases: Osteoarthritis
Since MSCs can differentiate into bone, cartilage, and adipose tissue, MSCs were tested as treatments for skeletal diseases such as bone defects soon after their discovery. Cellular replacement therapy was attempted after differentiating them into bone or cartilage at the site of pathology. Although this use of MSCs is not the focus of my review, it seems relevant to talk about osteoarthritis, a disease associated with both tissue degeneration and chronic inflammation. In this disorder, the anti-inflammatory, immune regulatory effects of MSCs could be beneficial and the cells could potentially regenerate cartilage as well. In fact, the anti-inflammatory effect might be required for regeneration to occur.
Osteoarthritis is a very common debilitating disease that affects approximately 30 million people in the US. The disease occurs when the cartilage at the end of the bones gradually wears down and an inflammatory reaction - because of bone-on-bone contact - develops. The lubricating synovial fluid becomes thick and inflammatory cells are invading the joint. Bone spurs also develop and increase the pain and inflammation (see42). The disease can occur in any joint, but the most common and functionally devastating is in the knee or hip joint which affects mobility in addition to having to live with chronic pain. There is no cure, but maintenance of mobility is achieved by rest, physiotherapy, support (ie, use of walker or cane; weight loss) and NSAIDs to fight the inflammation and pain. Eventually, surgery is the only final solution, but even artificial joints have a life span and a limitation of who can tolerate the long procedure of surgery and recovery. This is, why the disease was one of the first targets of possible MSC therapy. Good reviews are available that summarized MSC trials regarding OA up to 2020.43,44 While at the beginning most studies used autologous cells, as the knowledge and the know-how developed, the more convenient and consistent use of allogeneic cells became more popular. Unfortunately, like in most of the cases when MSCs were used in clinical trials, there are not enough large-scale, double-blind studies that used the same cells in similar patient populations that a result of effectiveness could be determined. Most trials (summarized in43,44) confirmed though that the treatment is safe and results in a significant decrease in pain (without NSAIDs) and improvement of function. Continuing the testing of MSC as cellular therapy in OA are 14 ongoing clinical trials (see Table 3). Among these, the largest trial is in the US (with the goal of recruiting 480 patients) is a randomized multicenter single-blind trial comparing a variety of sources for stem cells (NCT03818737). Unfortunately, the COVID-19 epidemic significantly delayed recruitment, so the original completion date of December 31, 2021, will be delayed.
Table 3.
Osteoarthritis.
Gastrointestinal System
The gastrointestinal (GI) tract is a major target of the immune system in GVHD. In addition to GVHD, there are several other chronic immune-related diseases of the GI system with no known cure. Most of these can be controlled but the quality of patients’ lives is not ideal. These diseases include several GI inflammatory (autoimmune) diseases as well as liver and gall bladder problems (inflammatory bowel disease such as Crohn’s disease and ulcerative colitis and autoimmune hepatitis and cholangitis). Currently, inflammatory bowel diseases are treated with steroids and anti-TNF agents that must be given for life and have side effects in a significant fraction of patients. Better treatments are needed. Although little is known about the development of these diseases it is generally accepted that dysregulation of the immune system drives their pathology. Diet, toxins, and genetic factors probably contribute to them as well.
Intravenous allogeneic MSCs were given to 16 patients suffering from active luminal Crohn’s disease (CD). Eleven patients had clinical improvement in their disease and 7 of these had significant endoscopic improvement. Only one patient had an adverse effect, but it was not thought to be related to the MSC infusion.45
Adipose-derived MSCs have been given locally to several hundred patients with refractory peri-anal CD46,47 and they appeared to be safe. The trials have been summarized in a review written in 2017.48 The phase III clinical trial by Panes et al described in Lancet in 2016 is an MSC success story.49 The trial included over 100 patients with Crohn’s disease derived peri-anal fistulas in each (placebo and treatment) of 2 arms. The double-blind, placebo-controlled study recruited people in 49 countries. Those in the active arm had single doses of allogeneic, adipose-derived, expanded cells injected into their lesions and based on the results of the trial, the European Medicines Agency (EMA) approved the use of the MSC preparation tested (named Aloficel) as a treatment for peri-anal fistulas. Although the exact mechanism of the effect of MSCs is not clear, it has been reported that there is a change in the ratio of the different T-cell subsets in CD and it pushes the balance toward pro-inflammatory activity.50 MSCs are likely to tip the balance back toward normal function as reported in other diseases.9,51
While CD is localized in the small intestine, ulcerative colitis (UC) is the equivalent IBD of the large intestine and the efficacy of MSCs has been tested in this disorder as well. Seven human studies have been summarized in a 2019 review that includes a description of animal data as well.52 The authors concluded that the therapy is safe and promising.
Both innate and adaptive immunity are thought to participate in the pathogenesis of UC. Based on studies of patient biopsies, IL-13 has been suggested to play a key role in the deficiency of the epithelial barrier function in UC.53 Interleukin-5 produced by natural killer cells was also found to contribute to barrier dysfunction.54
Acute pancreatitis is a dangerous and hard to treat disease.55 To date, the use of MSCs in this condition has only been studied in animals. A novel mechanism of action of MSCs in acute pancreatitis in rats has been suggested by Tu et al. They found that MSCs affect AQP-1 aquaporin production decreasing intestinal edema associated with pancreatitis. Thus, the MSCs that travel to sites of injury may reduce local inflammation.56 These trials are summarized in Table 4.
Table 4.
Gastrointestinal diseases.
Cardiovascular System
Over the last decade, a few trials were initiated to test the potential of using MSCs in patients with heart failure. There are 4 clinical trials with published results and 3 going on at present. These studies originally focused on the ability of MSCs to stimulate tissue regeneration versus regulating immune function. The first results (NCT00768066) came from a small number of patients who received trans-endocardial injections of MSCs, bone marrow cells (BMCs), or a placebo. Only the MSC injected patients showed functional improvement and the treatment seemed safe.57 Butler et al injected ischemia tolerant MSCs (itMScs) which had been cultured in hypoxic conditions (NCT02467387).58 This was reported in an earlier study to increase the migration of the cells toward damaged tissue.59 In subjects given MSCs intravenously, there was a decrease in the number of natural killer (NK) cells and an increase in left ventricular ejection fraction.58 These observations were interesting since most workers in the field thought that iv. MSCs would not be useful in heart failure and opted for local treatments instead.
In another study patients with non-ischemic dilated cardiomyopathy (DCM) were given MSCs percutaneously (NCT01392625). The results suggested that stromal-derived factor 1 (SDF-1) secreted by the cells might modulate inflammatory cytokine concentrations60 and vascular endothelial progenitors and showed that allogeneic MSCs can do this twice as efficiently as autologous cells. In an earlier clinical study, the same group reported that a decrease in circulating inflammatory cytokine concentrations results in an improved quality of life and performance measures in an elderly frail population with DCM.61
Finally, a combination of MSCs and cardiac c-kit positive stem cells were administered together to patients with ischemic heart failure in a multi-center trial (NCT02501811). The combination of the 2 cell types seemed to result in clinical improvement without affecting the structure and function of the left ventricle, indicating a possibly paracrine, systemic mechanism. The authors suggest further studies on how the combination of these 2 different cell types might improve function through secretion of beneficial immunomodulatory, anti-inflammatory, antiapoptotic, or other factors.62
The 2 presently ongoing phase I clinical trials (NCT02408432, NCT02962661) both focus on the treatment of cardiomyopathy due to damage caused by a chemotherapeutic agent (anthracycline).
Dermatological Diseases
The first short review summarizing the potential of MSCs in treating dermatological diseases was published in 2015.63 Since then, numerous clinical trials were initiated, and some have been completed already. Fifteen trials are under way (Table 5). A number of diseases have been targeted including psoriasis, scleroderma, epidermolysis bullosa (EB), atopic dermatitis, and diabetic skin ulcers; (see64). While these problems are relatively common, there are other, rarer serious diseases without treatment that should also be examined in the future.
Table 5.
Dermatological diseases.
Psoriasis, one of the most common skin diseases has been characterized by increased angiogenesis in hyperplastic epidermal lesions which are sites of infiltrating immune cells. The pathophysiology of psoriasis is very complex, but the involvement of a variety of inflammatory cytokines and the role of immune cells (T cells, dendritic cells, neutrophils) have been well established; (see65). Case reports of 2 patients treated with UC MSCs were published in 2016. Successful treatment was followed by long (5 and 4 years thus far) relapse-free periods.66 In the same year another description of 2 patients was published, who were treated with autologous adipose tissue-derived MSCs. They had psoriasis vulgaris and psoriatic arthritis, respectively. No adverse effects were observed. The patient with psoriasis vulgaris improved and no longer required methotrexate. The one with psoriatic arthritis also responded to the MSCs but needed a combination of MSCs and monoclonal antibodies to drive TNFα levels down.67
Scleroderma is a chronic connective tissue disease in which too much collagen is made by tissues. The disease is characterized by the invasion of tissues by T cells, B cells, and macrophages, resulting in unbalanced cytokine and chemokine levels. The high pro-inflammatory cytokine concentrations drive fibrosis. Two cases of refractory scleroderma were treated with intravenous UC MSC infusions. The treatment was safe and there appeared to be a clinical improvement.68 A recent review by Escobar-Soto summarized the results of studies of 100 patients with scleroderma (systemic sclerosis) who were treated with MSCs and concluded that no definite conclusion can be reached without better-designed, larger studies. However, there were no significant adverse events reported, supporting the belief that MSC infusions are safe.69
Atopic dermatitis (AD) is a complex inflammatory skin disease with no known cure. MSCs were tested in AD patients and found useful. Intravenous infusions of umbilical cord MSCs resulted in a dose-dependent improvement of symptoms in a group of 34 patients. A decrease in serum IgE and eosinophilic cells were documented, and no adverse effects were reported following the treatments.70
Epidermolysis bullosa is a genetic disease in which the molecules that anchor the epidermis and dermis to one another are inefficient. Even small traumatic events cause the skin layers to separate, and painful blisters form that can then be infected. The disease ranges from mild to fatal and can be caused by mutations in one or more genes. Gene therapies are being explored. Meanwhile, MSC treatments have been tested and found beneficial.71-73 How the cells act in epidermolysis bullosa is unknown; (see64).
Deficient wound healing is another common problem in dermatology and is especially troublesome in diabetes (due to circulatory problems) and in geriatric patients. Wound healing starts with cytokines and chemokines release. This attracts neutrophils and macrophages to initiate debridement of the injured area. MSCs limit inflammation and tissue damage at sites of injury by decreasing IL-1 and TNFα production and T-cell proliferation. They also stimulate the proliferation of fibroblasts to promote healing.74 Several trials of BM-MSCs and UC-MSCs are ongoing for wound healing in diabetic patients. An agent that could help heal chronic wounds is much needed and there have been many animal studies and clinical trials of MSCs as cellular therapy. The fact that MSCs are present in the skin and participate in wound healing normally was an argument in favor of their use. A recent excellent review75 summarizes the animal data as well as the past and present clinical trials to test this idea and analyzes the challenges of such treatments. Most of these challenges are like in other MSC disease treatments (I will mention these in the Discussion) but using MSCs in wound healing might have some special requirements. The variety of sources of MSCs should be screened to find which would be optimal for use in wounds. Possibly find a specific subpopulation that has the best efficacy in this application. To adjust treatments (dose and timing) to the known phases of wound healing and to find the best scaffold to graft MSCs in chronic wounds is needed.75
Finally, the BMSCs have been shown to affect mast cell function76 which suggests that urticaria might be a target of MSC therapy.
Neurological Diseases
There are many neurodegenerative diseases. Basic and clinical scientists have hoped for decades that stem cells could be used to replace losses of cells in the nervous system because neurons cannot divide. Fetal stem cells were the first ones tried, but ethical issues surrounding their use led clinicians to study adult stem cells from bone marrow, adipose tissue, and umbilical cord instead. Giving the cells intravenously or intrathecally has been safe, but it has been hard to show efficacy consistently. It is likely that some of the beneficial effects seen have resulted from reduced inflammation as opposed to the replacement of dying cells with new ones.
There is not enough space to list the hundreds of clinical trials that have focused on treating neurological diseases with MSCs. Instead, I will give some examples and in Table 6 list ongoing trials in a few diseases to show the approaches and sources of cells in use. Given their immune suppressive effects, the most logical targets for MSCs are neurodegenerative diseases like multiple sclerosis (MS) in which the immune system attacks myelin proteins or strokes in which tissue damage causes local inflammation. There are 2 new (2021) phase I and phase I/II studies registered to explore regeneration and explore the safety and tolerability of MSC infusion into patients with MS, respectively in a small number of patients. One of these (NCT04749667) uses intrathecally applied autologous cells, while the other (NCT04956744) uses IMS001, a human embryonic cell-derived MSC, given intravenously.
Table 6.
Neurological diseases.
The other potentially promising neurological target I would like to mention here is stroke, where the rescue of neurons at the border of the lesion (penumbra) is the primary goal and seems more likely to be successful than hoping for stem cell-derived replacement of neurons. These studies were triggered by a variety of earlier basic science experiments suggesting that through paracrine effects MSCs might significantly improve recovery from stroke. This inference has led to studies using the secretomes of MSCs. The mixture of hormones/cytokines/ chemokines and even mRNA species might have beneficial effects. In fact, secretome therapy is now seen as a potential alternative to MSC treatment. How best to do this is a work in progress. A nice overview of how a potential stroke treatment evolved from searching for cell replacement to utilizing the anti-inflammatory effects of MSCs can be found in a comprehensive review by Stonesifer et al.77 A recent study by the same authors described how intracarotid infusions of BM-derived cultured NCS-01 cells protected rat cortical cells from oxygen deprivation-induced injury in vitro. Furthermore, in vivo experiments in rats revealed significant reductions of the infarct area accompanied by improvements in motor function when the cells were given as long as 3 days after the stroke. This could be very important in a clinical setting. The injected stem cells reached out with filopodia toward the damaged neurons and produced large amounts of bFGF and IL-6 that might be responsible for the observed changes.78 Based on the pre-clinical data outlined above, the FDA approved a trial of intra-carotid injections of NCS-01 cells in patients with ischemic strokes (NCT03915431).
MSC and Cancer
The role of fibroblasts/cancer stroma in tumors and the immunological effects of these cells have been studied extensively. I cannot describe these studies in detail but will refer to appropriate recent reviews on the subject. Fibroblasts are building blocks of all tissues, and cancer in any tissue is associated with fibroblasts. As described above in detail, MSCs can affect both innate and adaptive immune functions. Cancer is always surrounded by inflammatory cells, the extracellular matrix (ECM) is rebuilt, cell migration, cell proliferation is all altered affecting metastasis forming. For about 2 decades researchers wondered what the role of cancer stroma (fibroblasts) in cancer might be. Thinking of MSCs\' ability to reduce T-cell proliferation, one role might be to help the cancer cells by reducing the immune response and eliminating the attack by cytotoxic T cells. The idea that cancer might recruit stromal cells for that very reason seemed logical and has been studied broadly. The origin of tumor stroma is still not clear. Cancer-associated fibroblasts (CAF) can help cancer in many ways: suppressing immune response, inducing new vessel formation, changing the ECM to help migration/metastasis, and changing the microenvironment to benefit the cancer cells’ needs. The mechanisms of how MSCs can promote the growth of tumors are numerous.79 Cancer stroma can originate from local fibroblasts, circulating bone marrow-derived MSCs, pericytes around local vasculature, or vascular and lymphatic endothelium. The process is regulated by signals from the chemokines and cytokines around cancer, and since this environment changes constantly, the behavior and recruitment of fibroblasts do the same. If one tries to imagine this interaction it is almost impossible to do due to the differences between different kinds and stages of all cancers in addition to the differences between the immune system of the individual hosts. Another interesting question in cancer biology has been the role of senescent cells in cancer and the importance of the senescence-associated secretory phenotype (SASP) of the stroma. Ozcan et al demonstrated that the secretome of senescent stromal cells can suppress the proliferation of myeloma cells in vitro but only if they have not been in the company of the cancer cells previously. Once they are thus conditioned, the cancer cells seem to be able to eliminate or significantly decrease of their anti-tumor activity.80,81 All the above makes it very complicated to understand the best ways to try to utilize the immune-modifying activity of the tumor stroma (MSC) for cancer treatment. I want to refer the reader to excellent recent reviews on the topic that focus on the role of fibroblasts MSCs in human cancer82,83 and lists ongoing clinical trials.84,85
MSC-Derived Microvesicles/Exosomes in Clinical Trials
It has been known for some time that most mammalian cells release vesicles into their environment. These extracellular vesicles (EVs) contain proteins, lipids, and RNA and are divided into 2 major classes depending on their cellular origin and size: microvesicles that are shed off of the plasma membrane and smaller exosomes.86 Instead of using MSCs to treat patients, clinical investigators have begun to use MSC-derived EVs. I will discuss the pros and cons of doing this in the Discussion. Table 7 lists some of the applications of EVs in clinical trials to date.
Table 7.
Microvesicles/exosomes.
Discussion
Originally described as stromal cells in bone marrow Friedenstein,1 fibroblasts are found in most tissues11,12 including the BM where several subpopulations of fibroblasts were found to have different roles in producing collagen, supporting hematopoiesis, giving rise to bone, cartilage, and fat. A recent article gives a very detailed comparison of fibroblast populations in a variety of different tissues in mice based on their expression profile87 suggesting a lot of common and many unique features depending on the organ of origin. Bone marrow, adipose tissue, and umbilical cord-derived MSCs are easy to collect and expand in culture; thus, these sources of cells became the favorites for clinical use. Many excellent reviews have been published in the last decade on interactions between MSCs and immune cells. Below we give some examples and refer readers to more detailed specific accounts.
MSC’s Response to Cytokines and Chemokines
One important feature of MSCs is that they sense hypoxic and injured tissues and are attracted to them.88-90 Once the MSCs reach such tissues, they seem to sense the cellular and cytokine composition of the environment there and respond accordingly by regulating and coordinating the functions of the immune cells in the area.
The MSCs are equipped with a variety of receptors to be able to synthesize the appropriate response to the surrounding tissue (Fig. 1). They express many chemokine receptors, such as CCR1, CCR7, CCR9, CXCR4-6 all of which respond to their distinct ligands (many of which are also produced by MSCs (for details see91-93). Most of the chemokines will induce/ affect the migration of MSCs to injury sites. Once they arrive, their large array of receptors will respond to the actual cytokine environment through specific receptors (among these the TNFR1/2, IFN, TGFβR1, and 2 are the most studied).94,95 Since the MSCs used in most studies and trials are a mixed population of cells, researchers have long wondered if there is a subpopulation of MSCs that are immune-modulatory in nature or whether all MSCs are capable of this depending on the environment they are in. It has been suggested that a small percentage of MSCs—ones that are similar to pluripotent stem cells (called multilineage differentiating stress enduring (MUSE) cells) are the ones that recognize damage signals and migrate to sites of trouble.96,97 However, based on many studies, it does not seem likely that these MUSE cells could be responsible for all the immune-modulatory effects of MSCs, since these effects have been reported with non-selected, cultured cells from a variety of sources and MUSE cells are less than 1% of the MSC population. All MSCs seem to express a variety of pattern recognition receptors (TLRs) to respond to potentially harmful stimuli98 including TLR3 that responds to foreign double-stranded RNA.9,99 After migrating to the injury/attack site and receiving the input signal through one of its receptors, the MSC prepares the optimal “brew” of agents to bring the site back to homeostasis by regulating functions of the immune cells recruited by the injury (Fig.1). What do we know about these interactions?
Figure 1.
Summary of MSC’s (mesenchymal stem or stromal cells) effect on infectious/inflammatory environment. After sensing pathogens and/or inflammatory cytokines in their environment, the secretome of the MSC will work to re-balance the environment to non-inflammatory and pathogen-free state. Abbreviation: MSC: mesenchymal stromal cells.
T Cells
Nearly 20 years ago MSCs were shown to suppress the proliferation of CD4 and CD8 T cells in a mixed lymphocyte reaction (MLR). The T cells did not become apoptotic; in fact, they proliferated. The same effect was observed when instead of co-culturing them, the bone marrow MSCs and T cells were separated in a transwell. This suggested that soluble factors such as hepatocyte growth factor (HGF) and transforming growth factor-beta (TGF-β) released by the MSCs4 were responsible for the effects seen. In the same year, another study showed that MSCs not only block proliferation but also inhibit T-cell responses to their cognate antigens.100 Later several subsets of CD4 and CD8 cells were found to interact with BMSCs. IL-17 produced by Th17 cells stimulates IL-17 receptors on the mouse and human BMSCs.101 In their in vitro work another group reported that MSCs can recruit, regulate, and help maintain the identity of Tregs,102 a feature that is the focus of a variety of clinical trials listed in a recent review.103 Our group showed that, in a Th2 driven allergic (asthmatic) environment, BMSCs produce TGF-β that likely in concert with recruited Tregs drives down eosinophil infiltration, Th2 cytokines, and allergy specific IgGs.104 Leukemia inhibitory factor (LIF) — described as an important player in transplantation tolerance — is also made by human MSCs and suppresses the proliferation of T cells in an MLR reaction.105
There are a few suggested mechanisms underlying the T-cell suppressive behavior of MSCs (see17). In humans, it is generally accepted now that IL-10 and indolamine 2,3 dioxygenase (IDO) are among the several mediators of the immune-suppressive behavior of MSCs. MSCs were shown to make IDO protein and they exhibit increased IDO activity upon stimulation with IFN-γ.18
Monocyte-induced activation appears to be necessary for the MSCs to achieve T-cell suppression and IL1-β may mediate this effect through downregulation of T-cell activation factors.19 Rasmusson et al have reported that IL2, IL10, and possibly prostaglandins may contribute to immune suppression by human MSCs.20 Sato’s group described the role of MSC-derived nitric oxide in mediating T-cell suppression,21 a finding later confirmed by Ren et al22 who added that when MSCs are stimulated by interferon-gamma and an additional pro-inflammatory cytokine (such as TNFα, IL1α, or β) they will produce NO and chemokines that attract T cells bearing the appropriate chemokine receptors. Once the T cells are attracted to the MSCs, MSC-derived NO inhibits their further proliferation. Both Sato and Ren worked with mouse MSCs, and they used knockout animals in their work.
Over time, additional factors have come to light that contribute to the MSC-driven inhibition of T-cell proliferation. Jones et al demonstrated that human MSCs arrest T cells in the G0/G1 cell cycle and decrease their pro-inflammatory environment.23 MSC-derived Galectin-1 (a cell/cell contact modulator) and Sema-3A (a chemo-repellant) were later found to bind to neuropilin 1 (NRP-1).24 Neuropilin-1 is constitutively expressed on the surface of T cells and when it binds to semaphorin, the cells arrest in G0/G1 cell cycle, which was the mechanism suggested also by Jones.23 Another important discovery in mice was described by Choi in 2011, who added another soluble factor to the known and ever-broadening arsenal of MSCs immune suppressive factors, TNF- alpha-induced protein 6 (TSG6 or TNFAIP6). TSG6 is a secretory protein that downregulates NF-κB signaling25 and thus decreases cell proliferation. In addition, it was also demonstrated that cell to cell contact with pro-inflammatory macrophages induces MSCs’ TSG6 production and results in more efficient suppression of CD4 T-cell proliferation26 in mice. Another interesting observation by Davies et al106 showed that MSCs can also secrete PD-L1 and PD-L2, ligands that modulate programmed cell death protein 1 (PD-1) on the surface of T cells involved in T-cell activation.
B Cells
MSCs have a variety of pattern recognition receptors 99 allowing them to respond to local signals and interact with lymphocytes. MSCs were reported to induce both regulatory and naïve B-cells while suppress activated and memory B-cells. This effect is mediated at least partially by soluble secreted factors.107,108 Co-culturing BMSCs and B-cells will lead to a suppression of B-cell response by arresting the cell cycle, thus blocking differentiation and reducing Ig production.109-111
NK Cells
Natural killer cells are the body’s first line of defense against viral attack and the interaction between BMSCs and NK cells depends on environmental factors. MSCs evade being destroyed by NK cells by upregulation of PGE2 and IDO as well as upregulation of their HLA I antigen that inhibits recognition by NK cells Resting or activated NK cells interact with BMSCs in different ways. At first, BMSCs inhibit the proliferation of NK cells induced by local IL2 and IL5 but they don’t affect the cytotoxic function of the NK cells already present. But when NK cells are already activated by IL-2 and IL-5 and are cocultured with BMSCs, the latter is able to also affect cytokine production, cytotoxicity, and the release of granzyme B containing vesicles from NK cells — which is another good example of how BMSCs sensor the environment and respond accordingly.99,112
Macrophages/Monocytes/Dendritic Cells
In addition to lymphocytes, the phagocytic myeloid cells are also affected by MSCs. MSCs change the character of macrophages from TNFα producing pro-inflammatory M1 to anti-inflammatory IL-10 producing M2. In septic mice, this seems to result from the release of PGE2 induced by activation of TLR4 in the MSCs. Stimulation of macrophage E2 and E4 receptors by the released PGE263 drives the change in the cells. A similar effect was recently seen when human bone marrow stem cells were incubated with pro-inflammatory airway macrophages in broncho-alveolar lavage fluid from sarcoidosis patients.35 In addition to PGE2, hepatocyte growth factor (HGF) also appears to play a role in modifying the function of macrophages by activating the ERK1/2 pathway.113 An MSC secreted antagonist to the interleukin-1 receptor (IL1RA)114 as well as IDO115 and TSG-625,116 may contribute to the effect as well. Intravenously infused MSCs have been shown to block the TLR4 induced activation of dendritic cells (DCs). This prevents cytokine secretion and migration of DCs to regional lymph nodes to present their antigen to T cells alleviating the inflammation.117
Neutrophils
Neutrophils are phagocytic myeloid cells that are attracted to microbes. They have an extensive arsenal of weapons at their disposal, including reactive oxygen molecules, bactericidal agents, and unique extracellular traps.118 These neutrophil extracellular traps (NETs) are made of DNA-derived extracellular fibers, which can physically trap the pathogens similarly to a fishnet trapping fish.
Neutrophils are attracted to sites of inflammation/infection by IL-8 and macrophage inhibitory factor (MIF) released by local or invading MSCs.119,120 MSCs then modulate NO-based oxidative damage caused by neutrophils, stimulate their phagocytic function, and decrease their apoptosis.119 In an allergic/inflammatory environment the increased histamine will stimulate the H1 receptor of the MSCs. This stimulation will result in increased secretion of IL8 by the MSCs that attract more neutrophils to the site. MSCs will also increase their IL-6 production that is a strong anti-apoptotic agent and will help to keep more live neutrophils in the immediate area121 leading to faster resolution of the inflammation/infection.
Mast Cells
Mast cells (MCs) are inflammatory cells of myeloid lineage that play a very significant role in allergic disorders including asthma, rheumatoid arthritis, and dermatological diseases. MSCs when they are in contact with them, suppress MC degranulation, inflammatory cytokine production, and chemotaxis. The effect is driven by increased Cox2 production by the BMSCs resulting in PGE2 release and stimulation E4 receptors on MCs.76
Use of MSCs Versus MSC Medium/Exosome
Bone marrow MSCs are a heterogeneous cell population. Whether the cells that make up this population have fixed phenotypes or can change in response to environmental alterations is not known. In the former case, we should learn how to purify and exploit various MSC subtypes. In the latter case, we should try to discover how to differentiate the cells according to our needs—ie, make cells that are strong immunomodulators, or bone, cartilage, or fat cell precursors. To solve these problems, we will have to find specific combinations of markers to use in identifying cells of interest.
The advantage of MSCs over exosomes should be obvious. MSCs respond to signals in their environment.9,122 Exosomes have a fixed set of contents and, presumably, are optimal for treating some conditions but not others. While they may not be as flexible as MSCs, one can imagine building a bank of EVs that have been tested and found to be optimal for treating certain conditions. Unlike cells, frozen aliquots of such EV preparations can easily and quickly be readied for administration. Both more basic science research and testing are necessary to achieve this. However, we know that when MSCs are injected and “reprogram” the area of injury (immune cells, endothelial cells, bacteria, etc.) then the conversation between the MSC and its environment continues and is not steady. The MSC will change its cytokine/small nucleic acid, anti-bacterial peptide, etc. production depending on the first response from the environment after the MSC arrived. This is something we cannot do with exosomes — they remain as they were harvested. Thus, we lose some flexibility of the applied MSCs. Interestingly, it has been shown that even if the MSC is short-lived, when the immune cells phagocytose the apoptotic MSCs — the phagocytic host immune cells will produce IDO that is needed for immune suppression. The authors suggested either screening patients for their ability to kill MSCs or treating them with pre-treated apoptotic MSCs.123 However, similarly to the exosome scenario — we lose the plasticity of the infused MSC since it is not likely that apoptotic cells would respond to the environmental signal the same way how healthy MSCs would. While secretomes cannot respond to environmental signals, they can teach us how MSCs have responded to specific perturbations. Consequently, they are worth examining. For instance, studies of amniotic fluid-derived stem cell secretomes have shown that a variety of miRNAs may inhibit apoptotic factors and promote neuronal survival following strokes. Based on this, one may be able to select or prime cells that are especially efficient at making factors with beneficial effects on strokes or other disorders.124,125
State of Trials and State of the Field
On December 13, 2016, the 21st Century Cures Act was signed into law with the hope of significantly accelerating product development and speeding up their use in patients. The law provides means to the FDA to expedite programs for use of certain biological products. Proposals to be included in this concept were included in the RMAT (Regenerative Medicine Advanced Therapy) process that aims to see novel clinical trials designs and the use of “Real-world evidence”. Within this framework, the FDA so far granted RMAT designation to 64 proposals. Only 54 of these have available information and 4 of those included studying MSC therapy focusing on their immune-regulatory roles. These 4 proposals include (companies are in alphabetical order):
Athersys proposed to study ARDS (NCT04367077) with 400 and stroke (NCT03545607) with 300 participants; both conditions with interventional clinical trials using iv infusion of bone marrow stem cells, called Multistem. The proposed completion date of the phase II/III and 3 trials are December 2023 and September 2022, respectively. Fortress Biotec in Texas uses autologous bone marrow mononuclear cells to alleviate symptoms of childhood (NCT01851083, 47 participants) and adult (NCT02525432, 55 participants) traumatic brain injury. However, this phase I/II study uses a mixture of BM cells, thus the results might or might not be relevant for MSCs. The Australian company, Mesoblast applies trans-endocardial delivery of human bone marrow-derived allogeneic MPCs in patients (466) with chronic heart failure in their phase III study (NCT02032004). Finally, the fourth RMAT proposal was by Vericel Corporation to treat chronically dilated heart (NCT01670981, NCT00765518) and osteonecrosis (NCT00505219) using their unique mixture of bone marrow MSCs and M2, anti-inflammatory, macrophages in a multi-cellular approach. The company’s proprietary technology expands the MSCs and the M2 macrophages from the patient’s bone marrow while retaining the other hematopoietic cells. The MSC/M2 cells regulate the immune response and secrete factors that have pro-angiogenic and regenerative effects and bear anti-inflammatory actions.
Most of the trials seeking to exploit the unique features of MSCs took place in the last 2 decades. Initially, the cells were tested for regenerative abilities, but later their immune-modulatory effects were appreciated and many immune-related diseases (autoimmune diseases, sepsis, chronic inflammatory disease, etc.) were identified as potential targets. There were over 1000 clinical trials word-wide to test these opportunities and very few consistent therapeutic successes emerged. As of today, there are 2 approved clinical applications for MSCs. In 2016, stem cells were approved for use in steroid-resistant acute GVHD in Japan. The history of this trial and the results from the first 3 years can be found in a recent review.126 The cells (called Temcell) used in the Japanese trial and for clinical therapy are “off-the-shelf” MSCs produced from healthy human donor bone marrow samples. The harvesting, culture, and storage conditions used are like those used but used unsuccessfully by Osiris (Prochymal). Compared to thymoglobulin treatments, the responses to MSCs are similar, but there is less non-relapse mortality in the MSC group due to a lower incidence of infections.126 The other success story as I said in the GI section above, was the use of allogeneic, off-the-shelf adipose-derived MSCs in the treatment of complex peri-anal fistulas in Crohn’s disease, which received approval in 2018 by the EMA. At present, there are 24 phase III clinical trials in 10 different countries listed at Clinicaltrials.gov for a wide variety of diseases. All but 3 were first posted in the last 3 years. To have more approved treatments using off-the-shelf MSCs (BM, adipose-derived, umbilical cord, placenta) there are lessons that we should have learned from the nearly 1000 unsuccessful or marginally successful trials performed to date. We need to learn how best to culture the cells and how to expand them so that they retain their activities. We know that they can be “primed”, but we do not know which methods increase their activities most. The therapeutic target should be selected carefully and tested in animal models when possible. The inclusion and exclusion criteria should be carefully selected. The source of the stem cells, how they are cultured, and how many passages they undergo before use should be well controlled and compared. The route of administration (local or systemic) should be picked thoughtfully. The primary and secondary endpoints should be well thought out and the study should be well powered. Right now, the only sure thing is that the stem cells appear to do no harm. It is hard to make this claim for many other therapies.
In summary, MSCs can potentially be used to treat a variety of diseases. They appear to be safe to give and respond to environmental cues by secreting factors that rebalance harmful inflammatory conditions. In individualizing their responses, they are “smarter” than drugs which have fixed efficacies and toxicities.
Acknowledgment
This work was supported by the DIR (Division of Intramural Research) of the NIH, NIDCR (project number ZIA DE000714). The graphics were done using BioRender (biorender.com). The author thanks Dr. Michael J. Brownstein for his help with editing the manuscript.
Conflict of Interest
The author declared no potential conflicts of interest.
Data Availability
No new data were generated or analyzed in support of this research.
References
- 1. Friedenstein AJ, PiatetzkyS, II, Petrakova KV. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol. 1966;16(3):381-390. [PubMed] [Google Scholar]
- 2. Dominici M, Blanc K Le, Mueller I, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315-317. [DOI] [PubMed] [Google Scholar]
- 3. Lazarus HM, Haynesworth SE, Gerson SL, et al. Ex vivo expansion and subsequent infusion of human bone marrow-derived stromal progenitor cells (mesenchymal progenitor cells): implications for therapeutic use. Bone Marrow Transplant. 1995;16(4):557-564. [PubMed] [Google Scholar]
- 4. Nicola M D, Carlo-Stella C, Magni M, et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood. 2002;99(10):3838-3843. [DOI] [PubMed] [Google Scholar]
- 5. Bartholomew A, Sturgeon C, Siatskas M, et al. Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo. Exp Hematol. 2002;30(1):42-48. [DOI] [PubMed] [Google Scholar]
- 6. Klyushnenkova E, Mosca JD, Zernetkina V, et al. T cell responses to allogeneic human mesenchymal stem cells: immunogenicity, tolerance, and suppression. J Biomed Sci. 2005;12(1):47-57. [DOI] [PubMed] [Google Scholar]
- 7. Le Blanc K, Rasmusson I, Sundberg B, et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet. 2004;363(9419):1439-1441. [DOI] [PubMed] [Google Scholar]
- 8. Lazarus HM, Koc ON, Devine SM, et al. Cotransplantation of HLA-identical sibling culture-expanded mesenchymal stem cells and hematopoietic stem cells in hematologic malignancy patients. Biol Blood Marrow Transplant. 2005;11(5):389-398. [DOI] [PubMed] [Google Scholar]
- 9. Mezey E, Nemeth K. Mesenchymal stem cells and infectious diseases: smarter than drugs. Immunol Lett. 2015;168(2):208-214. [DOI] [PubMed] [Google Scholar]
- 10. Lindner U, Kramer J, Rohwedel J, et al. Mesenchymal stem or stromal cells: toward a better understanding of their biology? Transfus Med Hemother. 2010;37(2):75-83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Tavakoli S, Ghaderi Jafarbeigloo HR, Shariati A, et al. Mesenchymal stromal cells; a new horizon in regenerative medicine. J Cell Physiol. 2020;235(12):9185-9210. [DOI] [PubMed] [Google Scholar]
- 12. Markov A, Thangavelu L, Aravindhan S, et al. Mesenchymal stem/stromal cells as a valuable source for the treatment of immune-mediated disorders [in eng]. Stem Cell Res Ther. 2021;12(1):192. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
- 13. Gruhn B, Brodt G, Ernst J. Extended treatment with mesenchymal stromal cells-frankfurt am main in a pediatric patient with steroid-refractory acute gastrointestinal graft-versus-host disease: case report and review of the literature. J Pediatr Hematol Oncol. 2021;43(3):e419-e425. [DOI] [PubMed] [Google Scholar]
- 14. Doring M, Cabanillas Stanchi KM, Lenglinger K, et al. Long-term follow-up after the application of mesenchymal stromal cells in children and adolescents with steroid-refractory graft-versus-host disease. Stem Cells Dev. 2021;30(5):234-246. [DOI] [PubMed] [Google Scholar]
- 15. Bonig H, Kuci Z, Kuci S, et al. Children and adults with refractory acute graft-versus-host disease respond to treatment with the mesenchymal stromal cell preparation “MSC-FFM”-outcome report of 92 patients. Cells. 2019;8(12): 8121577. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Bader P, Kuci Z, Bakhtiar S, et al. Effective treatment of steroid and therapy-refractory acute graft-versus-host disease with a novel mesenchymal stromal cell product (MSC-FFM). Bone Marrow Transplant. 2018;53(7):852-862. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Keating A. How do mesenchymal stromal cells suppress T cells? Cell Stem Cell. 2008;2(2):106-108. [DOI] [PubMed] [Google Scholar]
- 18. Meisel R, Zibert A, Laryea M, et al. Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase-mediated tryptophan degradation. Blood. 2004;103(12):4619-4621. [DOI] [PubMed] [Google Scholar]
- 19. Groh M, Maitra B, Szekely E, et al. Human mesenchymal stem cells require monocyte-mediated activation to suppress alloreactive T cells. Exp Hematol. 2005;33(8):928-934. [DOI] [PubMed] [Google Scholar]
- 20. Rasmusson I, Ringden O, Sundberg B, et al. Mesenchymal stem cells inhibit lymphocyte proliferation by mitogens and alloantigens by different mechanisms Exp Cell Res. 2005;305(1):33-41. [DOI] [PubMed] [Google Scholar]
- 21. Sato K, Ozaki K, I O, et al. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood. 2007;109(1):228-234. [DOI] [PubMed] [Google Scholar]
- 22. Ren G, Zhang L, Zhao X, et al. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell. 2008;2(2):141-150. [DOI] [PubMed] [Google Scholar]
- 23. Jones S, Horwood N, Cope A, et al. The antiproliferative effect of mesenchymal stem cells is a fundamental property shared by all stromal cells. J Immunol. 2007;179(5):2824-2831. [DOI] [PubMed] [Google Scholar]
- 24. Lepelletier Y, Lecourt S, Renand A, et al. Galectin-1 and semaphorin-3A are two soluble factors conferring T- cell immunosuppression to bone marrow mesenchymal stem cell. Stem Cells Dev. 2010;19(7):1075-1079. [DOI] [PubMed] [Google Scholar]
- 25. Choi H, Lee RH, Bazhanov N, et al. Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-kappaB signaling in resident macrophages. Blood. 2011;118(2):330-338. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26. Li Y, Zhang D, Xu L, et al. Cell-cell contact with proinflammatory macrophages enhances the immunotherapeutic effect of mesenchymal stem cells in two abortion models. Cell Mol Immunol. 2019;16(12):908-920. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Krasnodembskaya A, Song Y, Fang X, et al. Antibacterial effect of human mesenchymal stem cells is mediated in part from secretion of the antimicrobial peptide LL-37. Stem Cells. 2010;28(12):2229-2238. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Cruz FF, Rocco PRM. The potential of mesenchymal stem cell therapy for chronic lung disease. Expert Rev Respir Med. 2020;14(1):31-39. [DOI] [PubMed] [Google Scholar]
- 29. Weiss DJ, Casaburi R, Flannery R, et al. A placebo-controlled, randomized trial of mesenchymal stem cells in COPD. Chest. 2013;143(6):1590-1598. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Sisson TH, Mendez M, Choi K, et al. Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis. Am J Respir Crit Care Med. 2010;181(3):254-263. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Chambers DC, Enever D, Ilic N, et al. A phase 1b study of placenta-derived mesenchymal stromal cells in patients with idiopathic pulmonary fibrosis. Respirology. 2014;19(7):1013-1018. [DOI] [PubMed] [Google Scholar]
- 32. Tzouvelekis A, Paspaliaris V, Koliakos G, et al. A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis J Transl Med. 2013;11:171. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Chang YS, Ahn SY, Yoo HS, et al. Mesenchymal stem cells for bronchopulmonary dysplasia: phase 1 dose-escalation clinical trial. J Pediatr. 2014;164(5):966-972 e966. [DOI] [PubMed] [Google Scholar]
- 34. Namba F. Mesenchymal stem cells for the prevention of bronchopulmonary dysplasia. Pediatr Int. 2019;61(10):945-950. [DOI] [PubMed] [Google Scholar]
- 35. McClain Caldwell I, Hogden C, Nemeth K, et al. Bone marrow-derived mesenchymal stromal cells (MSCs) modulate the inflammatory character of alveolar macrophages from sarcoidosis patients. J Clin Med. 2020;9(1): 9010278. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36. Qin H, Zhao A. Mesenchymal stem cell therapy for acute respiratory distress syndrome: from basic to clinics. Protein Cell. 2020;11(10):707-722. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Wilson JG, Liu KD, Zhuo H, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med. 2015;3(1):24-32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Abreu SC, Rolandsson Enes S, Dearborn J, et al. Lung inflammatory environments differentially alter mesenchymal stromal cell behavior. Am J Physiol Lung Cell Mol Physiol. 2019;317(6):L823-L831. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39. Hashemian SR, Aliannejad R, Zarrabi M, et al. Mesenchymal stem cells derived from perinatal tissues for treatment of critically ill COVID-19-induced ARDS patients: a case series. Stem Cell Res Ther. 2021;12(1):91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Ellison-Hughes GM, Colley L, O’Brien KA, et al. The role of MSC therapy in attenuating the damaging effects of the cytokine storm induced by COVID-19 on the heart and cardiovascular system. Front Cardiovasc Med. 2020;7:602183. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41. Khoury M, Cuenca J, Cruz FF, et al. Current status of cell-based therapies for respiratory virus infections: applicability to COVID-19. Eur Respir J. 2020;55(6):2000858. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42. Arden N, Nevitt M. Osteoarthritis: epidemiology. Best Pract Res: Clin Rheumatol. 2006;20(1):3-25. [DOI] [PubMed] [Google Scholar]
- 43. Mautner K, Carr D, Whitley J, et al. Allogeneic versus autologous injectable mesenchymal stem cells for knee osteoarthritis: review and current status. Tech Orthop. 2019;34(4):244-256. [Google Scholar]
- 44. Song Y, Zhang J, H X, et al. Mesenchymal stem cells in knee osteoarthritis treatment: a systematic review and meta-analysis. J Orthop Translat. 2020;24:121-130. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45. Forbes GM, Sturm MJ, Leong RW, et al. A phase 2 study of allogeneic mesenchymal stromal cells for luminal Crohn’s disease refractory to biologic therapy. Clin Gastroenterol Hepatol. 2014;12(1):64-71. [DOI] [PubMed] [Google Scholar]
- 46. Lightner AL. The present state and future direction of regenerative medicine for perianal Crohn’s disease. Gastroenterology. 2019;156(8):2128-2130.e2124. [DOI] [PubMed] [Google Scholar]
- 47. Panés J, García-Olmo D, Assche G V, et al. Long-term efficacy and safety of stem cell therapy (Cx601) for complex perianal fistulas in patients with Crohn’s disease. Gastroenterology. 2018;154(5):1334-1342.e1334. [DOI] [PubMed] [Google Scholar]
- 48. Adak S, Mukherjee S, Sen D. Mesenchymal stem cell as a potential therapeutic for inflammatory bowel disease- myth or reality? Curr Stem Cell Res Ther. 2017;12(8):644-657. [DOI] [PubMed] [Google Scholar]
- 49. Panés J, García-Olmo D, Assche G V, et al. Expanded allogeneic adipose-derived mesenchymal stem cells (Cx601) for complex perianal fistulas in Crohn’s disease: a phase 3 randomised, double-blind controlled trial. Lancet. 2016;388(10051):1281-1290. [DOI] [PubMed] [Google Scholar]
- 50. Brand S. Crohn’s disease: Th1, Th17 or both? The change of a paradigm: new immunological and genetic insights implicate Th17 cells in the pathogenesis of Crohn’s disease. Gut. 2009;58(8):1152-1167. [DOI] [PubMed] [Google Scholar]
- 51. Bernardo ME, Fibbe WE. Mesenchymal stromal cells and hematopoietic stem cell transplantation [in eng]. Immunol Lett. 2015;168(2):215-221. [DOI] [PubMed] [Google Scholar]
- 52. Shi X, Chen Q, Wang F. Mesenchymal stem cells for the treatment of ulcerative colitis: a systematic review and meta-analysis of experimental and clinical studies. Stem Cell Res Ther. 2019;10: 266. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 53. Heller F, Florian P, Bojarski C, et al. Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution Gastroenterology. 2005;129(2):550-564. [DOI] [PubMed] [Google Scholar]
- 54. Fuss IJ, Heller F, Boirivant M, et al. Nonclassical CD1d-restricted NK T cells that produce IL-13 characterize an atypical Th2 response in ulcerative colitis. J Clin Investig. 2004;113(10):1490-1497. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 55. Kawakubo K, Ohnishi S, Kuwatani M, et al. Mesenchymal stem cell therapy for acute and chronic pancreatitis. J Gastroenterol. 2018;53(1):1-5. [DOI] [PubMed] [Google Scholar]
- 56. Tu XH, Huang SX, Li WS, et al. Mesenchymal stem cells improve intestinal integrity during severe acute pancreatitis. Mol Med Rep. 2014;10(4):1813-1820. [DOI] [PubMed] [Google Scholar]
- 57. Heldman AW, DiFede DL, Fishman JE, et al. Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial. JAMA. 2014;311(1):62-73. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 58. Butler J, Epstein SE, Greene SJ, et al. Intravenous allogeneic mesenchymal stem cells for nonischemic cardiomyopathy: safety and efficacy results of a phase II-a randomized trial. Circ Res. 2017;120(2):332-340. [DOI] [PubMed] [Google Scholar]
- 59. Vertelov G, Kharazi L, Muralidhar M, et al. High targeted migration of human mesenchymal stem cells grown in hypoxia is associated with enhanced activation of RhoA. Stem Cell Res Ther. 2013;4(1):5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 60. Premer C, Wanschel A, Porras V, et al. Mesenchymal stem cell secretion of SDF-1α modulates endothelial function in dilated cardiomyopathy. Front Physiol. 2019;10: 1182. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 61. Tompkins BA, Difede DL, Khan A, et al. Allogeneic mesenchymal stem cells ameliorate aging frailty: a phase II randomized, double-blind, placebo-controlled clinical trial. J Gerontol A Biol Sci Med Sci. 2017;72(11):1513-1522. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62. Bolli R, Mitrani RD, Hare JM, et al. A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial. Eur J Heart Fail. 2021;23(4):661-674. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63. Nemeth K, Mezey E. Bone marrow stromal cells as immunomodulators. A primer for dermatologists. J Dermatol Sci. 2015;77(1):11-20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64. Golchin A, Farahany TZ, Khojasteh A, et al. The clinical trials of mesenchymal stem cell therapy in skin diseases: an update and concise review. Curr Stem Cell Res Ther. 2019;14(1):22-33. [DOI] [PubMed] [Google Scholar]
- 65. Brandon A, Mufti A, Gary Sibbald R. Diagnosis and management of cutaneous psoriasis: a review. Adv Skin Wound Care. 2019;32(2):58-69. [DOI] [PubMed] [Google Scholar]
- 66. Chen H, Niu JW, Ning H-M, et al. Treatment of psoriasis with mesenchymal stem cells. Am J Med. 2016;129(3):e13-e14. [DOI] [PubMed] [Google Scholar]
- 67. De Jesus MM, Santiago JS, Trinidad CV, et al. Autologous adipose-derived mesenchymal stromal cells for the treatment of psoriasis vulgaris and psoriatic arthritis: a case report. Cell Transplant. 2016;25(11):2063-2069. [DOI] [PubMed] [Google Scholar]
- 68. Wehbe T, Saab MA, Chahine N A, et al. Mesenchymal stem cell therapy for refractory scleroderma: a report of 2 cases. Stem Cell Investig. 2016;3:48. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69. Escobar-Soto CH, Mejia-Romero R, Aguilera N, et al. Human mesenchymal stem cells for the management of systemic sclerosis. Systematic review. Autoimmun Rev. 2021;20(6):102831. [DOI] [PubMed] [Google Scholar]
- 70. Kim HS, Lee JH, Roh KH, et al. Clinical trial of human umbilical cord blood-derived stem cells for the treatment of moderate-to-severe atopic dermatitis: phase I/IIa studies. Stem Cells. 2017;35(1):248-255. [DOI] [PubMed] [Google Scholar]
- 71. Conget P, Rodriguez F, Kramer S, et al. Replenishment of type VII collagen and re-epithelialization of chronically ulcerated skin after intradermal administration of allogeneic mesenchymal stromal cells in two patients with recessive dystrophic epidermolysis bullosa. Cytotherapy. 2010;12(3):429-431. [DOI] [PubMed] [Google Scholar]
- 72. El-Darouti M, Fawzy M, Amin I, et al. Treatment of dystrophic epidermolysis bullosa with bone marrow non-hematopoeitic stem cells: a randomized controlled trial. Dermatol Ther. 2016;29(2):96-100. [DOI] [PubMed] [Google Scholar]
- 73. Petrof G, Lwin SM, Martinez-Queipo M, et al. Potential of systemic allogeneic mesenchymal stromal cell therapy for children with recessive dystrophic epidermolysis bullosa. J Investig Dermatol. 2015;135(9):2319-2321. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 74. Hu MS, Borrelli MR, Lorenz HP, et al. Mesenchymal stromal cells and cutaneous wound healing: a comprehensive review of the background, role, and therapeutic potential. Stem Cells Int. 2018;2018:6901983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 75. Huang YZ, Gou M, Da LC, et al. Mesenchymal stem cells for chronic wound healing: current status of preclinical and clinical studies. Tissue Eng Part B Rev. 2020;26(6):555-570. [DOI] [PubMed] [Google Scholar]
- 76. Brown JM, Nemeth K, Kushnir-Sukhov NM, et al. Bone marrow stromal cells inhibit mast cell function via a COX2-dependent mechanism Clin Exp Allergy. 2011;41(4):526-534. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 77. Stonesifer C, Corey S, Ghanekar S, et al. Stem cell therapy for abrogating stroke-induced neuroinflammation and relevant secondary cell death mechanisms. Prog Neurobiol. 2017;158:94-131. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 78. Kaneko Y, Lee JY, Tajiri N, et al. Translating intracarotid artery transplantation of bone marrow-derived NCS-01 cells for ischemic stroke: behavioral and histological readouts and mechanistic insights into stem cell therapy. Stem Cells Transl Med. 2020;9(2):203-220. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 79. Koh BI, Kang Y. The pro-metastatic role of bone marrow-derived cells: a focus on MSCs and regulatory T cells. EMBO Rep. 2012;13(5):412-422. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 80. Alessio N, Aprile D, Squillaro T, et al. The senescence-associated secretory phenotype (SASP) from mesenchymal stromal cells impairs growth of immortalized prostate cells but has no effect on metastatic prostatic cancer cells. Aging. 2019;11(15):5817-5828. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 81. Ozcan S, Alessio N, Acar MB, et al. Myeloma cells can corrupt senescent mesenchymal stromal cells and impair their anti-tumor activity Oncotarget. 2015;6(37):39482-39492. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 82. Kalluri R. The biology and function of fibroblasts in cancer Nat Rev Cancer. 2016;16(9):582-598. [DOI] [PubMed] [Google Scholar]
- 83. Koliaraki V, Prados A, Armaka M, et al. The mesenchymal context in inflammation, immunity and cancer. Nat Immunol. 2020;21(9):974-982. [DOI] [PubMed] [Google Scholar]
- 84. Hmadcha A, Martin-Montalvo A, Gauthier BR, et al. Therapeutic potential of mesenchymal stem cells for cancer therapy. Front Bioeng Biotechnol. 2020;8:43. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 85. Lim SK, Khoo BY. An overview of mesenchymal stem cells and their potential therapeutic benefits in cancer therapy. Oncol Lett. 2021;22(5):785. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 86. Kao CY, Papoutsakis ET. Extracellular vesicles: exosomes, microparticles, their parts, and their targets to enable their biomanufacturing and clinical applications. Curr Opin Biotechnol. 2019;60:89-98. [DOI] [PubMed] [Google Scholar]
- 87. Buechler MB, Pradhan RN, Krishnamurty AT, et al. Cross-tissue organization of the fibroblast lineage. Nature. 2021;593(7860):575- 579. [DOI] [PubMed] [Google Scholar]
- 88. Newman RE, D Y, LeRoux MA, et al. Treatment of inflammatory diseases with mesenchymal stem cells. Inflamm Allergy Drug Targets. 2009;8(2):110-123. [DOI] [PubMed] [Google Scholar]
- 89. Rochefort GY, Delorme B, Lopez A, et al. Multipotential mesenchymal stem cells are mobilized into peripheral blood by hypoxia. Stem Cells. 2006;24(10):2202-2208. [DOI] [PubMed] [Google Scholar]
- 90. Sordi V. Mesenchymal stem cell homing capacity. Transplantation. 2009;87(9 Suppl):S42-S45. [DOI] [PubMed] [Google Scholar]
- 91. Ahmadian Kia N, Bahrami AR, Ebrahimi M, et al. Comparative analysis of chemokine receptor’s expression in mesenchymal stem cells derived from human bone marrow and adipose tissue. J Mol Neurosci. 2011;44(3):178-185. [DOI] [PubMed] [Google Scholar]
- 92. Galipeau J. Macrophages at the nexus of mesenchymal stromal cell potency: the emerging role of chemokine cooperativity. Stem Cells. 2021;39(9):1145-1154. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 93. Honczarenko M, Le Y, Swierkowski M, et al. Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. Stem Cells. 2006;24(4):1030-1041. [DOI] [PubMed] [Google Scholar]
- 94. Le Blanc K, Davies LC. Mesenchymal stromal cells and the innate immune response Immunol Lett. 2015;168(2):140-146. [DOI] [PubMed] [Google Scholar]
- 95. Rothweiler R, Basoli V, Duttenhoefer F, et al. Predicting and promoting human bone marrow MSC chondrogenesis by way of TGFβ receptor profiles: toward personalized medicine. Front Bioeng Biotechnol. 2020;8: 618. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 96. Alessio N, Özcan S, Tatsumi K, et al. The secretome of MUSE cells contains factors that may play a role in regulation of stemness, apoptosis and immunomodulation [in Eng]. Cell Cycle. 2017;16(1):33-44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 97. Dezawa M. The muse cell discovery, thanks to wine and science [in Eng]. Adv Exp Med Biol. 2018;1103:1-11. [DOI] [PubMed] [Google Scholar]
- 98. de Castro LL, Lopes-Pacheco M, Weiss DJ, et al. Current understanding of the immunosuppressive properties of mesenchymal stromal cells. J Mol Med. 2019;97(5):605-618. [DOI] [PubMed] [Google Scholar]
- 99. Le Blanc K, Mougiakakos D. Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol. 2012;12(5):383-396. [DOI] [PubMed] [Google Scholar]
- 100. Krampera M, Glennie S, Dyson J, et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood. 2003;101(9):3722-3729. [DOI] [PubMed] [Google Scholar]
- 101. Huang W, Russa V La, Alzoubi A, et al. Interleukin-17A: a T-cell-derived growth factor for murine and human mesenchymal stem cells. Stem Cells. 2006;24(6):1512-1518. [DOI] [PubMed] [Google Scholar]
- 102. Diianni M. Mesenchymal cells recruit and regulate T regulatory cells. Exp Hematol. 2008;36(3):309-318. [DOI] [PubMed] [Google Scholar]
- 103. Negi N, Griffin MD. Effects of mesenchymal stromal cells on regulatory T cells: current understanding and clinical relevance. Stem Cells. 2020;38(5):596-605. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 104. Nemeth K, Keane-Myers A, Brown JM, et al. Bone marrow stromal cells use TGF- to suppress allergic responses in a mouse model of ragweed-induced asthma. Proc Natl Acad Sci USA. 2010;107(12):5652-5657. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 105. Nasef A, Mazurier C, Bouchet S, et al. Leukemia inhibitory factor: role in human mesenchymal stem cells mediated immunosuppression. Cell Immunol. 2008;253(1-2):16-22. [DOI] [PubMed] [Google Scholar]
- 106. Davies LC, Heldring N, Kadri N, et al. Mesenchymal stromal cell secretion of programmed death-1 ligands regulates T cell mediated immunosuppression. Stem Cells. 2017;35(3):766-776. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 107. Franquesa M, Mensah FK, Huizinga R, et al. Human adipose tissue-derived mesenchymal stem cells abrogate plasmablast formation and induce regulatory B cells independently of T helper cells. Stem Cells. 2015;33(3):880-891. [DOI] [PubMed] [Google Scholar]
- 108. Carreras-Planella L, Monguió-Tortajada M, Borràs FE, et al. Immunomodulatory effect of MSC on B cells is independent of secreted extracellular vesicles. Front Immunol. 2019;10: 1288. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 109. Fan L, Hu C, Chen J, et al. Interaction between mesenchymal stem cells and B-cells. Int J Mol Sci. 2016;17(5):650. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 110. Rafei M, Hsieh J, Fortier S, et al. Mesenchymal stromal cell-derived CCL2 suppresses plasma cell immunoglobulin production via STAT3 inactivation and PAX5 induction. Blood. 2008;112(13):4991-4998. [DOI] [PubMed] [Google Scholar]
- 111. Corcione A, Benvenuto F, Ferretti E, et al. Human mesenchymal stem cells modulate B-cell functions. Blood. 2006;107(1):367-372. [DOI] [PubMed] [Google Scholar]
- 112. Spaggiari GM, Capobianco A, Becchetti S, et al. Mesenchymal stem cell-natural killer cell interactions: evidence that activated NK cells are capable of killing MSCs, whereas MSCs can inhibit IL-2-induced NK-cell proliferation. Blood. 2006;107(4):1484-1490. [DOI] [PubMed] [Google Scholar]
- 113. Chen PM, Liu KJ, Hsu PJ, et al. Induction of immunomodulatory monocytes by human mesenchymal stem cell-derived hepatocyte growth factor through ERK1/2. J Leukoc Biol. 2014;96(2):295-303. [DOI] [PubMed] [Google Scholar]
- 114. Luz-Crawford P, Djouad F, Toupet K, et al. Mesenchymal stem cell-derived interleukin 1 receptor antagonist promotes macrophage polarization and inhibits B cell differentiation. Stem Cells. 2016;34(2):483-492. [DOI] [PubMed] [Google Scholar]
- 115. Francois M, Romieu-Mourez R, Li M, et al. Human MSC suppression correlates with cytokine induction of indoleamine 2,3-dioxygenase and bystander M2 macrophage differentiation. Mol Ther. 2012;20(1):187-195. [DOI] [PubMed] [Google Scholar]
- 116. English K. Mechanisms of mesenchymal stromal cell immunomodulation. Immunol Cell Biol. 2013;91(1):19-26. [DOI] [PubMed] [Google Scholar]
- 117. Chiesa S, Morbelli S, Morando S, et al. Mesenchymal stem cells impair in vivo T-cell priming by dendritic cells. Proc Natl Acad Sci USA. 2011;108(42):17384-17389. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 118. Teng TS, Ji AL, Ji XY, et al. Neutrophils and immunity: from bactericidal action to being conquered. J Immunol Res. 2017;2017:9671604. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 119. Joel MDM, Yuan J, Wang J, et al. MSC: immunoregulatory effects, roles on neutrophils and evolving clinical potentials. Am J Transl Res. 2019;11(6):3890-3904. [PMC free article] [PubMed] [Google Scholar]
- 120. Planat-Benard V, Varin A, Casteilla L. MSCs and inflammatory cells crosstalk in regenerative medicine: concerted actions for optimized resolution driven by energy metabolism. Front Immunol. 2021;12: 626755. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 121. Nemeth K, Wilson T, Rada B, et al. Characterization and function of histamine receptors in human bone marrow stromal cells. Stem Cells. 2012;30(2):222-231. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 122. Bernardo ME, Fibbe WE. Mesenchymal stromal cells: sensors and switchers of inflammation. Cell Stem Cell. 2013;13(4):392-402. [DOI] [PubMed] [Google Scholar]
- 123. Galleu A, Riffo-Vasquez Y, Trento C, et al. Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation. Sci Transl Med. 2017;9(416):1-11. [DOI] [PubMed] [Google Scholar]
- 124. Castelli V, Antonucci I, D, ’Angeloet al. Neuroprotective effects of human amniotic fluid stem cells-derived secretome in an ischemia/reperfusion model. Stem Cells Transl Med. 2021;10(2):251-266. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 125. Crowley MG, Liska MG, Borlongan CV. Stem cell therapy for sequestering neuroinflammation in traumatic brain injury: an update on exosome-targeting to the spleen. J Neurosurg Sci. 2017;61(3):291-302. [DOI] [PubMed] [Google Scholar]
- 126. 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] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No new data were generated or analyzed in support of this research.