Preclinical studies: MSCs in respiratory virus-related lung injury
| Reference | Experimental model, route of infection, type of virus | MSC source, passage, number, administration route, timing of treatment | Time of outcome analysis | Adjuvant therapy | Outcome | Mechanisms of action | Control Group |
| Darwish et al., 2013 | C57BL/6 mice 7–10 weeks IN infection Influenza A/PuertoRico/8/34 (mouse- adapted H1N1) or Influenza A/Mexico/410 8/2009 (swine-origin pandemic H1N1) | Mouse BM -MSCs (P6-P9) Human BM – MSCs (P3) 2.5×105 cells 5×105 cells IV (tail vein) Single dose Day −2, 0, 2, 5 post infection | Day 7 or when euthanasia criteria was met | Oseltamivir 2.5 mg·kg−1 Oral gavage Once daily 5 days | Prophylatic and therapeutic syngeneic and xenogeneic administration of MSCs: Failed to improve survival, Failed to affect weight loss, and Failed to decrease lung parenchyma inflammation and BALF cell counts. | Non-specified (soluble mediators) | No |
| Gotts et al., 2014 | C57BL/6 mice 7–10 weeks IN infection Influenza A/Puerto Rico/8/34 (mouse-adapted H1N1) | Mouse BM–MSCs (P7 or less) Human BM– MSCs (P7 or less) 5×105 cells IV (Retro-orbital injection) IT (Data not shown) Two doses Either: Day 5 and 6 post infection, or Day 2 and 3 post infection (data not shown) | Days 7, 9 or 11 | No | Mouse MSCs: Prevented influenza- induced thrombocytosis, Caused a modest reduction in lung viral load on day 7, Early (data not shown) and late syngeneic and xenogeneic intravenous administration of MSCs: Failed to affect weight loss. Failed to decrease lung water. Failed to decrease BALF inflammation, and Failed to improve lung histology Intratracheal administration increased the severity of model data not shown). | Non-specified (soluble mediators) | No |
| Chan, 2016 | BALB/c mice 6–8 weeks - young 8–12 months – old IN infection with Influenza A /Hong Kong/486/199 7(H5N1) | Human BM– MSCs (Passage not mentioned) 5×105 cells IV Single dose Day 5 post infection | Days 7, 10 or 18 | No | In aged mice, but not young mice, allogeneic MSCs: Increased survival, Reduced weight loss, Reduced lung histopathological lesions, Increased M2 macrophages in BALF, Reduced lung proinflammatory cytokines and chemokines (MCP-1, MCP-3, MIP-1 α, RANTES, IL-4, IL-17, TNF-α), and Reduced lung virus titers | Paracrine soluble mediators, partially due to Ang1 and KGF secretion | NIH 3T3 mouse embryo fibroblasts |
| Li et al., 2016 | C57BL/6 mice 6–8 weeks IN infection with Avian Influenza virus Hong Kong/2108/20 03 (H9N2) | Mouse BM-MSCs (P3-P10) 1×105 cells IV (tail vein) Single dose 30 min, or Day 1 post-infection | Day 3 | No | Regardless of time administration, syngeneic MSCs: Did not reduce lung virus titration, Increased survival rate, Decreased lung edema, Decreased histologic injury, Improved gas exchange, Reduced BALF chemokines and cytokines early administration: GM-CSF, MIG content, IL-1α, IFN-γ, IL-6, TNF- α, Reduced serum chemokines and cytokines early administration: MIG content, IL-1α, IFN- γ, IL-6, TNF- α, Early administration increased anti- inflammatory cytokine IL-10 in BALF and serum. | Non-specified (soluble mediators) | No |
| Khatri et al., 2016 | White-Duroc crossbred pigs 8 weeks IN infection with Swine/TX/98 Influenza virus - H3N2 and Swine/MN/08 (H1N1) | Pig BM-MSCs EVs (P3-P5) 80 μg·kg−1 body weight (produced by 10×106 MSCs) IT Single dose 12 h post- infection | Days 1 or 3 | No | BM-MSC-derived EVs: Decreased virus shedding in nasal swabs, Reduced influenza virus replication in the lungs, Prevent virus-induced production of pro- inflammatory cytokines (TNF-α, CXCL-10), Reduced histologic injury and lung edema. | Non-specified (extracellular vesicles) | No |
| Loy et al., 2019 | BALB/c mice 6–8 weeks IN infection with Influenza A/Hong Kong/486/1997 (H5N1) | Human UC–MSCs (P7 or less) 5×105 cells IV Single dose Day 5 post infection | Days 7, 10, 14 or 18 | No | UC-MSCs Failed to decrease lung virus titration, Failed to increase survival rate, Reduced body weight loss, Decreased lung edema, and Decreased BAL cytokines (IP-10, MCP-1, RANTES, IL-1β. | Paracrine soluble mediators, partially due to Ang1 and HGF secretion | NIH 3T3 mouse embryo fibroblasts |
Preclinical studies showing the effects of MSCs in virus-mediated lung injury. ALI: acute lung injury; Ang1: angiopoietin 1; BM: MSCs: bone marrow-derived mesenchymal stem (stromal) cells; CXCL-10: C-X-C motif chemokine; EV: extracellular vesicles; GM-CSF: granulocyte-macrophage colony-stimulating fator; IL:Interleukin; IN: Intranasal; IT: intratracheal; IP-10: interferon γ– induced protein 10; IV: Intravenous; MCP: monocyte chemoattractant; MIG: monokine induced by interferon-γ ; MIP: macrophage inflammatory protein; RANTES: Regulated upon Activation, Normal T Cell Expressed and Presumably Secreted; TNF: Tumor necrosis factor; UC-MSCs: umbilical cord-derived MSCs.