TABLE 1 Pre-clinical studies of MSCs in respiratory virus-related lung injury
First author, year [ref.] 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, 2013 [37] C57BL/6 mice aged 7–10 weeks, i.n. 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) or human BM- MSCs (P3), 2.5×105 or 5×105 cells·mouse−1, i.v. (tail vein), single dose, days −2, 0, 2 or 5 post infection Day 7 or when euthanasia criteria were met Oseltamivir 2.5 mg·kg−1, oral gavage, once daily for 5 days Prophylactic 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 Nonspecified (soluble mediators) No
Gotts, 2014 [38] C57BL/6 mice aged 7–10 weeks, i.n. infection, influenza A/Puerto Rico/8/34 (mouse-adapted H1N1) Mouse BM-MSCs (≤P7) or human BM-MSCs (≤P7), 5×105 cells·mouse−1, i.v. (retro-orbital injection) or i.t. (data not shown); two doses: 1) days 5 and 6 post infection, 2) days 2 and 3 post infection (data not shown) Days 7, 9 or 11 No Mouse MSCs prevented influenza-induced thrombocytosis and caused a modest reduction in lung viral load on day 7; early (data not shown) and late syngeneic and xenogeneic i.v. administration of MSCs failed to affect weight loss, failed to decrease lung water, failed to decrease BALF inflammation, and failed to improve lung histology; i.t. administration increased severity of model (data not shown) Nonspecified (soluble mediators) No
Chan, 2016 [39] BALB/c mice aged 6–8 weeks (young) or 8–12 months (old), i.n. infection, influenza A/Hong Kong/486/1997(H5N1) Human BM-MSCs (passage not mentioned), 5×105 cells·mouse−1, i.v., single dose, day 5 post infection Days 7, 10 or 18 No In older mice, but not younger mice, allogeneic MSCs increased survival, reduced weight loss, reduced lung histopathological lesions, increased M2 macrophages in BALF, reduced lung pro-inflammatory cytokines and chemokines (MCP-1, MCP-3, MIP-1α, RANTES, IL-4, IL-17, TNF-α), but did not reduce lung virus titres Paracrine soluble mediators, partially due to Ang-1 and KGF secretion NIH 3T3 mouse embryo fibroblasts
Li, 2016 [16] C57BL/6 mice aged 6–8 weeks, i.n. infection, avian influenza virus Hong Kong/2108/2003 (H9N2) Mouse BM-MSCs (P3–P10), 1×105 cells·mouse−1, i.v. (tail vein), single dose, 30 min or day 1 post infection Day 3 No Regardless of time of administration, syngeneic MSCs did not reduce lung virus titration, increased survival rate, decreased lung oedema, decreased histological injury, and improved gas exchange; early and late administration reduced BALF and serum cytokines (IL-6 and TNF-α); early administration reduced BALF chemokine (GM-CSF), reduced BALF and serum chemokines and cytokines (MIG, IL-1α, IFN-γ), and increased anti-inflammatory cytokine IL-10 in BALF and serum Nonspecified (soluble mediators) No
Khatri, 2018 [40] White Duroc crossbred pigs aged 8 weeks, i.n. infection, influenza virus swine/TX/98 (H3N2) and swine/MN/08 (H1N1) Pig BM-MSC extracellular vesicles (P3–P5), 80 μg·kg−1 body weight (produced by 10×106 MSCs), i.t., single dose, 12 h post infection Days 1 or 3 No BM-MSC-derived extracellular vesicles decreased virus shedding in nasal swabs, reduced influenza virus replication in the lungs, prevented virus-induced production of pro-inflammatory cytokines (TNF-α, CXCL-10), and reduced histological injury and lung oedema Nonspecified (extracellular vesicles) No
Loy, 2019 [41] BALB/c mice aged 6–8 weeks, i.n. infection, influenza A/Hong Kong/486/1997 (H5N1) Human UC-MSCs (≤P7) 5×105 cells·mouse−1, i.v., 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 oedema, and decreased BALF cytokines (IP-10, MCP-1, RANTES, IL-1β) Paracrine soluble mediators, partially due to Ang-1 and HGF secretion NIH 3T3 mouse embryo fibroblasts
MSCs: mesenchymal stem (stromal) cells; i.n.: intranasal; i.v.: intravenous; i.t.: intratracheal; BM: bone marrow-derived; UC: umbilical cord-derived; BALF: bronchoalveolar lavage fluid; MCP: monocyte chemoattractant; MIP: macrophage inflammatory protein; RANTES: regulated upon activation, normal T-cell expressed and presumably secreted; IL: interleukin; TNF: tumour necrosis factor; Ang-1: angiopoietin-1; KGF: keratinocyte growth factor; GM-CSF: granulocyte–macrophage colony-stimulating factor; MIG: monokine induced by interferon-γ; IFN: interferon; CXCL-10: C-X-C motif chemokine 10; IP-10: interferon γ-induced protein 10; HGF: hepatocyte growth factor.