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Table 2 Biological effect and molecular mechanisms of MSCs and MSC-EVs in preclinical and clinical studies looking into lung injury

From: Potential application of mesenchymal stem cells and their exosomes in lung injury: an emerging therapeutic option for COVID-19 patients

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
- 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
- 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)
- 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]
  1. RCT randomized, placebo-controlled; MSC, mesenchymal stem cell; ILD interstitial lung disease; ARDS acute respiratory distress syndrome; START the stem cells for ARDS treatment; ALI acute lung injury; IPF idiopathic pulmonary fibrosis; COPD chronic obstructive pulmonary disease; HPH hypoxia-induced pulmonary hypertension; PAH pulmonary artery hypertension; BPD bronchopulmonary dysplasia; BM bone marrow; UC umbilical cord; AD adipose tissue;, MMP-9 matrix metalloproteinase-9; Ang-2 angiopoeitin-2; RAGE receptor for advanced glycation end products; ccK18 caspase-cleaved cytokeratin-18; K18 cytokeratin-18; KGF keratinocyte growth factor; TGF-β1 transforming growth factor beta 1; TSG-6 tumor necrosis factor alpha-stimulated gene-6; UCF ultracentrifugation; IL1RN interleukin 1 receptor antagonist; AT1 Alveolar epithelial type I; AT2 Alveolar epithelial type II; AT-MSCs adipose-derived MSCs; hWJMSC human umbilical cord Wharton’s jelly MSC; IB intrabronchially; IT intratracheal; IV intravenous; IP intraperitoneal; BAL bronchoalveolar lavage; MIP-2 Macrophage Inflammatory Protein 2; EVLW extravascular lung water; STAT3 signal transducer and activator of transcription 3; IL-1β interleukin-1β; TLR3 toll-like receptor-3; COX2 prostaglandin-endoperoxide synthase 2; ARMMs arrestin domain-containing protein 1-mediated MVs; ASCs adipose-derived stem cells; IL1RN interleukin 1 receptor antagonist; WBCs white blood cells; RAGE receptor for advanced glycation end products