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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

- 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]

  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