Table 1.

Preclinical studies reported MSC-mediated mitochondrial transfer as the mechanism of action to treat diseases.

Reference	Donor cell	Target cell	Animal model (pathological condition)	Dosage	Route of administration	Mechanism of mitochondrial transfer	Therapeutic effect
37	Rat MSCs	Kidney (renal cells) Allogeneic	Rat with doxorubicin-mediated nephrotoxicity	8 × 106/mL mitochondria in 500 µL of respiration buffer	Applied directly below the cortex capsule (intraperitoneal administration)	Mitochondria were isolated before being injected into the kidney while the exact mechanism of mitochondrial uptake is yet unknown	- Reduce tubular protein accumulation and decrease proteinuria on day 6 - Decrease cellular oxidative stress and promote tubular regeneration - Increase antioxidant stress enzyme levels
27	Human UC-MSCs	Lymphoid cells (T cells) Xenogeneic	Mouse with graft-versus-host disease (GVHD)	12 × 106 mitocepted human PBMCs (MSC-mitochondria:PBMC ratios of 1:100, 1:25, and 1:10)	Injected through tail vein	No direct evidence (Mitochondrial transfer remains unaffected although inhibitors of TNT formation, gap junctions, hemichannels and macropinocytosis were applied, and no mitochondrial transfer was detected when incubated with conditioned media)	- Increase survival rate associated with a marked reduction in tissue injury (inflammation) on days 8 and 14
28	Human BM-MSCs	Lung tissues Xenogeneic	Mouse with LPS-induced lung injury (ARDS)	MSC-EVs (isolated from 5 × 105 or 1 × 106 MSCs suspended in 50 µl of PBS)	Injected through the tail vein	MSC-EVs	- Attenuate lung injury and restore lung tissue mitochondrial respiration after 24 hours
41	Human iPSC-MSCs	Retinal ganglion cells Xenogeneic	Mouse with mitochondrial complex I (NADH: ubiquinone oxidoreductase) deficiency	1 × 104 iPSC-MSCs in 0.5 μL PBS	Intravitreal injection	Not stated	- Prevent retinal function decline and loss of retinal ganglion cell layer at week 1 - Help to suppress the abnormal activation of Müller cells at week 4 and inflammatory status of the degenerating retina at week 1
29	Rat BM-MSCs	Motor neurons of the spinal cord Allogeneic	Rat with spinal cord injury (SCI)	10 μL BM-MSCs (1 × 106) and 10 μL mitochondria extracted from 3 × 106 BM-MSCs	Injected into the epicenter of the injured spinal cord using an electrode microneedle	Gap Junctional Intercellular Communication (GJIC)	- Improve locomotor function recovery by week 2 - Decrease apoptosis in the ventral horn of the spinal cord - Reduce the area of lesion cavity, glial scar, and the number of GFAP-positive cells - There is no significant difference in terms of efficacy between BMSCs group and the mitochondria group
43	Rat BM-MSCs	Cerebrovascular system Allogeneic	Rat with middle cerebral artery occlusion and reperfusion/injured cerebrovascular system (stroke)	5 × 105 MSCs in 10 μL of PBS	Intra-arterial injection (common carotid artery)	TNT-like structure	- Significantly reduce infarct volume - Improve motor function (average daily running distance) on day 7 - Display significantly higher microvessel densities in the peri-infarct area (promotion of angiogenesis) - Rescue mitochondrial respiration (improve mitochondrial activity) of brain microvessel
30	Rat BM-MSCs	Renal proximal tubular epithelial cells Allogeneic	Rat with streptozotocin-induced diabetic nephropathy	Mitochondria isolated from 1 × 106 MSCs and suspended in 100 µl of PBS	Injected under the renal capsule of the left kidney	Not stated	- Structural restoration of renal tubules by day 3
44	Mouse MSCs	Neural stem cells (NSCs) Allogeneic	Mouse with cisplatin-induced NSC damaged (chemotherapy)	3 μl of MSC cell suspension (1 × 106 cells per mouse per day)	Administered twice in each nostril	TNT-like structure	- Rescue NSCs from cisplatin-induced cell death in vitro and in vivo - Reverse cisplatin-induced loss of DCX+ neuroblasts 1 month after completion of cisplatin treatment
39	Human iPSC-MSCs	Lung tissues Xenogeneic	Mouse with ozone (oxidative stress)-induced mitochondrial dysfunction (COPD)	1 × 106 iPSC-MSCs	Injected intravenously	TNT-like structure	- Prevent ozone-induced mitochondrial dysfunction, airway hyper-responsiveness (AHR) and inflammation in mouse lungs after 21 hours
22	Human multipotent adipose-derived stem cells	Myocardium Xenogeneic	Mouse with MI	20 μL HBSS solution containing ~4.0 × 105 naïve MSCs	Injected into the myocardium surrounding the infarcted site (intracardiac delivery)	Not stated	- Reduce damage (protect from cell death), upregulate HO-1, and increase mitochondrial biogenesis after 24 hours
38	Human BM-MSCs	Alveolar macrophages Xenogeneic	Mouse with Escherichia coli pneumonia (ARDS)	1 × 106 MSCs	Injected intravenously through a tail vein in 100 µL of PBS or intranasally in 35 µL of PBS	TNT-like structure	- Enhance phagocytic capacity after 24 hours - Both routes showed similar efficacy
42	Human iPSC-MSCs	Corneal epithelial cells Xenogeneic	Rabbit with corneal alkali burn	1 × 105 MSCs seeded per scaffold	MSCs + matrix (acellular porcine cornea matrix) transplanted onto the corneal surface and sutured with 10-0 nylon	TNT-like structure	- Improve corneal wound healing after 48 hours
24	Human iPSC-MSCs and BM-MSCs	Airway epithelial cells Xenogeneic	Rat with cigarette smoke-induced lung damage (COPD)	Two doses of 3 × 106 human BM-MSCs or iPSC-MSCs in PBS	Injected intravenously through the tail vein	TNT-like structure	- Successfully attenuate airspace enlargement (reduce alveolar wall destruction), reduce mean linear intercept, and attenuate fibrosis by day 56
40	Mouse BM-MSCs	Bronchial epithelial cells Allogeneic	Mouse with rotenone (Rot)-induced airway (bronchial epithelial cells) injury and allergic airway inflammation (AAI)(asthma)	1 × 106 MSCs with fluorescence labeled mitochondria	Intratracheal (in 50 μL of media) administration for Rot-induced airway injury and intranasal (in 30 μL of media) administration for AAI	TNT-like structure	- Reduce caspase-3 and caspase-9 expression and lead to a consequent decrease in bronchial epithelial apoptosis and inflammation, reverse mitochondrial dysfunction and restore bioenergetics (increase in ATP levels in the lung), decrease cytochrome c in a cytosolic extract of the lung, and recover mitochondrial complex I and IV activities after 6 hours (airway injury model); - Attenuate AHR, decrease pro-inflammatory cytokines and restore ATP level, attenuate structural changes in the lungs by day 8 (AAI model)
14	Mouse BM-MSCs	Lung tissues (alveolar epithelium) Allogeneic	Mouse with LPS-induced acute lung injury (ALI)	2 × 105 BM-MSCs in 40 µl PBS	Intranasal instillation	Alveolus-attached BM-MSCs form Cx43-expressing nanotubes and microvesicles in a Ca2+-dependent manner	- Increase alveolar ATP within 5-8 hours - Reduce leukocytosis and albumin leakage in the bronchoalveolar lavage (BAL) - Increase survival time

Abbreviations: MSC, mesenchymal stem cell; iPSC, induced pluripotent stem cell; UC, umbilical cord; PBMC, peripheral blood mononuclear cell; TNT, tunneling nanotube; BM, bone marrow; LPS, lipopolysaccharide; ARDS, acute respiratory distress syndrome; PBS, phosphate-buffered saline; GFAP, glial fibrillary acidic protein; DCX, doublecortin; COPD, chronic obstructive pulmonary disease; MI, myocardial infarction; HBSS, Hank’s balanced salt solution; HO-1, Heme oxygenase-1; ATP, adenosine triphosphate; Cx43, connexin 43; Ca²⁺, calcium ion.