Table 1.

Preclinical studies describing implication of MSCs and MSC-EVs on mitochondrial transfer and MQC in cardiac, pulmonary, and hepatic injury.

Organ	Preclinical Model	Treatment	Outcome	Mechanism	References
Heart	Anthracycline-induced cardiomyopathy in mice	iPSC-MSCs and BM-MSCs	iPSC-MSC preserved heart tissue better than BM-MSCs.	Efficiency of Mt transfer TNT formation MSC expression of Miro1	Zhang et al., 2016 [158]
	Doxorubicin-induced injury in human cardiomyocytes in vitro	Co-culture or direct contact with MSC-EVs	Large MSC-EVs (>200 nm) ameliorated cardiomyocyte injury. Inhibition of Mt function in MSC-EVs attenuated efficacy.	Improved contractility ↑ ATP production ↑ Mt biogenesis	O’Brien et al., 2021 [163]
	Cardiomyocytes (H9c2) IRI in vitro	MSC-H9c2 co-culture	Marked resistance against IRI	↓ apoptosis ↑ Mt transfer from MSC to H9c2 via TNT formation	Han et al., 2016 [164]
	MI in mice	MSC-Mt transplanted in peri-infarct area	MSC-Mt preserved better cardiac function after MI then fibroblast derived Mt.	↑ Vessel density in MI area ↓ Apoptosis and endothelial cell senescence (via ERK pathway activation) ↓ Heart remodeling	Liang et al., 2023 [165]
	Co-culture of MSCs and cardiomyocytes or endothelial cells pretreated with H2O2. MI in mice	MSCs	Increased capacity of injured cells to combat oxidative stress. Reduced damage of infarcted mouse hearts.	Mitochondrial exchange between MSCs and damaged cells ↑ HO-1 ↑ mitochondrial biogenesis	Mahrouf-Yorgov et al., 2017 [150]
	Hibernating myocardium model without infarction in juvenile swine (surgical stenosis of the left anterior desc. coronary artery)	Epicardial MSC patch applied during coronary artery bypass graft	Improved myocardial function (measured by cardiac magnetic resonance imaging). Improved Mt function.	Improved Mt morphology ↑ Mt biogenesis and ATP production in cardiac tissue	Hocum et al., 2021 [166]
	MI in mice	MSCs preconditioned or not with Mt	MSCs primed with Mt had increased capacity to repair mouse myocardial infarct.	↑ Mitophagy of exogenous Mt ↑ Anti-inflammatory, proangiogenic and anti-fibrotic properties of MSCs primed with Mt.	Vignais et al., 2023 [167]
Lung	MSC/alveolar Mϕ direct co-culture	BM-MSCs	↑ Mϕ oxidative phosphorylation and phagocytosis	Mt transfer from MSCs to Mϕ by TNT formation	Jackson et al., 2017 [171]
	E. coli mouse ARDS model	BM-MSCs	↑ Mϕ phagocytosis Antibacterial effect	Mt from MSC aquired by lung Mϕ through TNT formation ↑ Phagocytic activity of Mϕ positive for MSC Mt	Jackson et al., 2016 [147]
	Mϕ and MSC non-contact co-culture stimulated with LPS or BALF from ARDS patients ARDS mouse model	MSCs Alveolar Mϕ cultured with and without MSC-EVs	↓ Cytokine production ↑ M2-like Mϕ marker expression ↓ Pulmonary inflammation ↓ Lung injury	↑ Mϕ phagocytic capacity Involvement of Mt in Mϕ & CD44 in MSC-EVs Crucial role of Mt in Mϕs and MSC-EVs	Morrison et al., 2017 [160]
	Primary cells and human lung cuts exposed to endotoxin or plasma of ARDS patients (in vitro) ARDS mouse LPS model	MSC-EVs	Improvement of increased cell permeability and Mt dysfunction ↓ Lung injury Restoration of alveolar-capillary barrier	Normalization of oxidative phosphorylation EVs with dysfunctional Mt was ineffective. Mt transfer and restoration of Mt function	Dutra–Silva et al., 2021 [172]
	Acute lung IRI rat model Lung epithelial cell line exposed to H/R injury (in vitro)	AD-MSCs and iPSC-MSCs	Similar lung protection with both AD-MSCs and iPSC-MSCs ↓ Lung injury score ↓ Inflammation cells	↓ Mitochondrial damage/cell apoptosis, autophagy, and oxidative stress ↓ Drp-1, Mt Bax/caspase3/8/9 and authophagy pathways (in vitro)	Lin et al., 2020 [173]
	ASMCs exposed to cigarette smoke media COPD mouse model (exposure to ozon)	iPSC-MSCs	↓ Mt ROS ↓ Airway inflammation and hyperresponsiveness	Mt transfer to donor cells ↑ Mt function	Li et al., 2018 [175]
	COPD mouse model (mice exposed to cigarette smoke for 10 days) BEAS2B-mMSC co-cultures	MSCs, MSC-EVs, MSC + MSC-EVs	↓ Bronchial epithelial damage ↓ Inflammatory cellular infiltration	↑ Mitofusin 1 and 2 ↑ Mt transfer ↓ Pro-inflammatory cytokines Same changes confirmed in co-culture settings	Maremanda et al., 2019 [176]
	Asthma mouse model	MSCs (naïve, over-expressing or knockout for Miro-1)	↓ Allergic inflammation and hyperresponsiveness of airways ↓ Lung injury	Mt transfer from MSCs to bronchial epithelial cells; Rho-GTPase Miro1-dependent process	Ahmad et al., 2014 [156]
	Asthma mouse model	BM-MSCs	↓ Lung inflammation ↓ Goblet cells mucus hyper-production Improved lung morphology	↓ Eosinophils and allergo-inflammatory cytokines ↓ Asthma induced mitochondrial gene expression ↑ Mt function	Huang et al., 2021 [177]
	Asthma mouse model	MSCs preconditioned or not with serum of asthma patients	↓ Lung inflammation ↓ Lung fibrosis ↑ Lung tissue regeneration	↑ Expression of TGFβ, IDO-1, TSG-6 by hMSC-serum ↑ fission ↓ respiratory capacity of Mt ↑ MSC apoptosis and their phagocytosis by Mϕ ↑ M2 Mϕ polarization	Abreu at al., 2023 [178]
	Co-culture of alveolar Mϕ and MSCs or MSC-EVs (in vitro) Mouse severe emphysema model	MSCs or MSC-EVs from healthy (H) and emphysematous (E) donor mice	Immunomodulatory effects ↑ IL-10 Improvement of cardiorespiratory dysfunction with MSC-EVs only from H donors	Abnormal Mt in E-MSCs and E-EVs—elongated, less functional and produced ↑ ROS vs. Mt from H-MSCs and H-EVs H-EVs showed better efficacy in comparison with H-MSCs, since they could access smaller airways, unreachable for MSCs.	Antunes et al., 2021 [179]
	ELBW infants with/without BPD (n = 39) UC-MSCs taken and studied in vitro	Endogenous MSCs isolated	MSCs with: Mt dysfuction ↓ ATP production and mytophagy ↓ Mt survival associated with BPD risk in ELBW infants.	Mt abnormalities may cause endogenous MSC pool depletion and disruptions in ELBW infant lungs.	Hazra et al., 2022 [180]
	IPF patients IPF (bleomycin) mouse model	Endogenous BM-MSCs isolated from IPF patients and age-mathed controls	BM-MSCs from IPF patients have signs of senescence with Mt dysfunction and DNA damage IPF BM-MSCs secreated pro-fibrotic factors and increased illness severity and inflammation in mice	Mt fragmentation ↓ Mt oxygen consumption and bioenergy ↑ IL-6, IL-8, IL-1β ↑ Pro-fibrotic factors	Cardenes et al., 2018 [181]
Liver	IRI in mice Hepatocites in vitro subjected to H/R injury	MSCs MSC-CM	↓ Liver injury Improved liver function ↓ Hepatocellular apoptosis	↓ ROS in tissue ↑ Parkin/PINK1 mitophagy ↑ ATP production by AMPKα activation	Zheng et al., 2020 [7]
	IRI in rats Hepatocyte cell culture	MSC-EVs	↑ Hepatic recovery ↓ Neutrophil infiltration and respiratory burst ↓ Oxidative stress	Mt transfer and Mt-located antioxidant enzyme (manganese superoxide dismutase (MnSOD) ↓ ROS—induced hepatocyte apoptosis and cell death in vitro	Yao et al., 2019 [184]
	IRI in specimen of human liver grafts (peri-operative) Mouse IRI	MSC-EVs	Liver graft morphology and function were better preserved Improved liver IRI in mice	↓ Liver graft inflammation and NET formation ↓ NET formation ↓ Netosis Mt transfer from EVs to intrahepatic neutrophils and their MQ control regulation	Lu et al., 2022 [185]
	D-Galactose induced hepatic disorder in rats Mt isolated from liver	UC-MSCs	Improved liver morphology and function Improved Mt respiration, ΔΨm and ATP production	↓ Histological lessions and liver enzymes ↑ Mt bioenergy and antioxidant capacity through Nrf2/HO-1 pathway	Yan et al., 2017 [186]
	Rat BDL cirrhosis	MSCs, naïve and tranducted with PRL-1	Liver regeneration Improved liver function Better efficacy of MSC-PRL-1 compared to naïve MSCs	↑ Metabolic state and Mt biogenesis of MSC-PRL-1 ↑ Engraftment, Mt DNA, biogenesis and ATP production in hepatocytes	Kim et al., 2020 [187]
	Rat BDL cirrhosis	MSCs, naïve and tranducted with PRL-1	↑ Oxidative capacity of MSC-PRL-1 MSC-PRL-1 vs. naïve MSCs improved further liver function and had greater antifibrotic effect	↑ Mt biogenesis and Mt lactate of MSC-PRL-1 MSC-PRL-1 have greater antioxidant effect vs. naïve MSCs	Kim et al., 2023 [188]
	Mouse NAFLD and diabetes (induced by high fat diet and streptozotocin) Hepatocytes treated with palmitic acid (in vitro)	MSC-CM	Improvement of insulin resistance and liver morphology ↓ Liver inflammation ↓ Cell apoptosis	↑ Liver antioxidant capacity ↑ Mt function in liver cells Crucial role of Sirt1 in cell protection	Yang et al., 2021 [190]
	Steatohepatitis in mice Hepatocytes and MSC co-culture	BM-MSCs	↓ Hepatocyte lipid content of ~40% ↓ Mt and peroxisomal dysfunction	Donation of Mt to hepatocytes Mt transfer from MSCs to hepatocytes by TNT formation	Hsu et al., 2020 [192]
	Steatohepatitis in mice	MSCs	Switch from liver lipid storage to its utilization	Donation of Mt to the hepatocytes Restoration of hepatocyte metabolism and oxidative capacity	Nickel et al., 2022 [191]
	Steatohepatitis in mice	MSCs	Improved liver morphology and metabolic function	Improvement of impaired Mt morphology and function ↑ Liver metabolic capacity and host gene shifting	Newell et al., 2018 [193]
	MSCs + fibroblasts (from Mt disease patients) −co-culture	MSCs	Improved Mt morphology and function	Inverting abundance of Mt fission toward fussion Mt state	Newell et al., 2018 [193]

Legend: ↑ increase; ↓ decrease.