Disease | Study and/or cell type | Postulated Mechanism of MSC action | Route of MSC and/or MSC-MV administration | EV isolation | Reference |
---|---|---|---|---|---|
Clinical studies | |||||
 ARDS | - RCT pilot study - Allogeneic AT-MSCs | - Decrease in surfactant protein D (SP-D) - Decrease in Il-6, Il-8 (not statistically significant) | - IV dose of 1 × 106 cells/kg | N.A. | [121] |
 Bronchopulmonary dysplasia (BPD) | - Phase I dose-escalation trial - UC-MSCs | - Reduction of IL-6, IL-8, MMP-9, TNF-α, and TGF-β1 in tracheal aspirates at day 7 | - Intratracheal administration - In nine preterm infants. - The first three patients were given a low dose (1 × 107 cells/kg) of cells - The next six patients were given a high dose (2 × 107 cells/kg) | N.A. | [122] |
 COPD | - RCT pilot study - Allogeneic MSCs (Prochymal; Osiris Therapeutics Inc.) | - Decrease in levels of circulating CRP (significant) - Levels of circulating TNF-α, IFN-γ, IL-2, IL-4, IL-5, and IL-10 were at or below limits of assay detection (preventing meaningful analysis) - Levels of circulating TGF-β and CRP did not differ significantly between baseline to years 1 or 2 in either treatment group | - 62 patients were randomized to double-blinded IV infusions - Patients received four monthly infusions (100 × 106 cells/infusion) and were subsequently followed for 2 years after the first infusion | N.A. | [123] |
 ARDS | - The START trial was a multi-center, open-label, dose-escalation phase 1 clinical trial - BM-MSCs | - Decrease in IL-6, RAGE, and Ang-2 levels (dose-independent) | - Three patients were treated with low dose MSCs (1million cells/kg), IV - Three patients received intermediate dose MSCs (5 million cells/kg), IV - Three patients received high dose MSCs (10 million cells/kg, IV) | N.A. | [124] |
 ARDS | - Non-randomized, pilot study (2 patients) - BM-MSCs | - Decrease in ccK18 and K18 - Decline in pro-inflammatory miRNAs in circulating EVs (miR-409-3P, 886-5P, 324-3P, 222, 125A-5P, 339-3P, 155) - Increased levels of circulating CD4+CD25highCD127low TRegs were observed in both patients’ peripheral blood | - 2 × 106 cells/kg IV | N.A. | [125] |
Preclinical studies | |||||
 ALI (endotoxin induced/E. coli) | Human BM-MSC | - Reduction in neutrophils and MIP-2 levels in the BAL - KGF-expressing MV transfer to injured alveolus - Reduced EVLW, improved lung endothelial barrier permeability and restored alveolar fluid clearance - -Restoration of the total cellular level and the apical membrane expression of αENaC | - 30 μl of MVs released by 1.5–3 × 106 serum starved MSCs - IT and IV routes - Ex vivo human lung and Human AT2 Cells. - IT dose: 750,000 MSCs | UCF (3000 rpm/Beckman Coulter Optima L-100XP) | [126] |
 ARDS (E. coli endotoxin) | Human BM-MSCs | - Increased M2 macrophage marker expression (CD206) - increased phagocytic capacity - EV-mediated mitochondrial transfer | - Ex vivo (murine) - EVs released by 15 × 106 MSCs over 48 h | UCF (10,000–100,000 xg) | [127] |
 Caecal ligation and puncture sepsis model (lung injury) | - Human UC-MSCs (IL-1β pretreatment) | - Induced M2 polarization - Exosomal miR-146a transfer to macrophages | - IV - 30 μg exosomes - 1 × 106 MSCs | UCF (Beckman Optima L-80 XP) | [128] |
 E. coli pneumonia-induced ALI | Human BM-MSCs | - KGF-expressing EV transfer/CD44 receptor dependent - Increased monocyte phagocytosis (antimicrobial) - Reduced the total bacterial load, inflammation, and lung protein permeability in the injured alveolus in mice - Decreased TNF- - Restoration of intracellular ATP levels in injured human AT2 (primary human AT2 culture) - TLR3 prestimulation increased mRNA expression for COX2 and IL-10 | - 10 μl per 1 × 106 MSCs - 30 or 60 μl MV, instilled IT - 90 μl MV, injected IV | UCF | [129] |
 Silicosis-induced lung injury/silica-exposed mice | - Human BM-MSCs - Mouse MSCs | - EVs outsource mitophagy, improve mitochondria bioenergetics via ARMMs - Represses TLR signaling in macrophages - Repress the production of inflammatory mediators via TLRs and NF-kB pathway (miR-451) - Prevent the recruitment of Ly6Chi monocytes and reduces IL-10 and TGF-β secretion (pro-fibrotic) by these cells in the lung of silica-exposed mice | - 40 μg protein (3 × 1011 EVs), IV | UCF | [130] |
 Emphysema/elastase-induced COPD model | Human AD-MSCs | - EV transfer to alveolar epithelium-FGF2 signaling | - IT - 1 mg nanovesicle from 7 × 107 ASCs (30 × 106 nanovesicle generated) | UCF (100,000×g force). Nanovesicle 100-nm | [131] |
 ALI (HPH) | - Mouse BM-MSCs - Human UC-MSCs | - EV transfer to endothelial cells suppress STAT3 signaling - Upregulation of the miR-17 superfamily of microRNA clusters - increased lung levels of miR-204 - Suppress pulmonary influx of macrophages | - IV - 0.1–10 μg MSC-derived exosomes | UCF (100 kDa cut-off/Millipore) | [132] |
 PAH | - Murine MSC(mMSC) - Human BM-MSCs | - Prevent and reverse pulmonary remodeling via EV miRNA transfer - Increased levels of anti-inflammatory, anti-proliferative miRs including miRs-34a, -122, -124, and -127. | - 25 μg of MVs, IV | UCF (100,000×g) | [133] |
 BPD (hyperoxia) | - Human UC-MSC - Human BM-MSCs | - Reduced mRNA levels of pro-inflammatory M1 macrophage markers (Tnfa, Il6, and Ccl5). - Enhanced M2 macrophage marker (Arg1) - Suppressed the hyperoxic induction of Cd206 - Significantly suppressed Retnla | - 0.9–3 μg protein, IV | UCF (OptiPrep/EVs 30–150 nm) | [134] |
 BPD (hyperoxia) | Human UC-MSCs | - TSG-6-expressing EV transfer - Decrease in IL-6, TNF-α, and IL-1β | - 2.4–2.8 μg EVs (obtained from 0.5–1 × 106 MSC), IP | UCF | [135] |
 Bleomycin (BLM)-induced lung inflammation and fibrosis | - Mouse BM-MSCs - Human BM-MSCs | - Block upregulation of IL-1 gene expression - IL1RN expressed by MSCs blocks release of TNF-α from activated macrophages - IL1RN is the principal IL-1 antagonist secreted by murine MSCs | - 5 × 105 MSCs, IV | N.A. | [136] |
 ALI (endotoxin induced) | Mouse-BM-MSCs | - Decreased total WBCs, neutrophils, MIP-2, EVLW, and TNFα - Increase expression of KGF mRNA in the injured alveolus - Increase IL-10 | - IT MSCs administration - 20,000 cells/100 μl for co-culture in vitro and transwell | -Transwell | [137] |
 ALI (primary human AT2) | Allogeneic human BM-MSCs | - Suppression of NFκB activity and further cytoskeletal re-organization of both actin and claudin 18 - Increase secretion of paracrine soluble factors angiopoietin-1 and Tie2 phosphorylation - Restoration of type II cell epithelial permeability to protein (Alveolar barrier integrity) | - Alveolar epithelial type II | Transwell plate | [138] |
 Pneumonia (E. coli) | Mouse BM-MSCs | - Decrease level of MIP-2 and TNFα, neutrophil degranulation in the alveolar space - Upregulate the concentration of lipocalin 2 expression (antimicrobial factor) in the alveolar space | - IT - 750,000 MSCs | N.A. | [139] |
 Pneumonia (E. coli) | Human MSCs | - MSC preferentially migrated to endotoxin-injured lung tissue - Increase KGF secretion - Human monocytes expressed the keratinocyte growth factor receptor - Reduced apoptosis of human monocytes through AKT phosphorylation - Increased the antimicrobial activity of the alveolar fluid (alveolar macrophage phagocytosis). - Decrease in TNF-α - Increase in IL-10 | - 5–10 × 106 human MSC, was instilled IB or IV (human ex vivo and in vitro monocyte studies) | N.A. | [140] |
 ALI (LPS-induced) | Mouse-BM-MSCs, human BM-MSCs | - Connexin 43-dependent mechanisms and transfer of viable mitochondria | - 2 × 105 BM-MSCs IT | N.A. | [141] |
 Acute lung injury | Rat-BM-MSCs | - Attenuated alveolar TNF α - Increase IL 10 | - 2 × 106 cells of MSCs, IV | N.A. | [142] |
 Acute lung injury | Clinical-grade human allogeneic-BM-MSCs | - Reduction in the airspace levels of RAGE, a marker of AT1 injury/activation - Increase secretion of KGF | - Ex vivo lung perfusion model (5 × 106 cells hMSCs, IB) | N.A. | [143] |