Table 2.

A comprehensive data on preclinical studies of stem cell therapy in ALI or ARDS

Source of stem cells	Animal models	Type of injury model	Route of delivery and dosage		Key findings/outcome	References
hBM-MSCs	C57BL/6 mice	H9N2 avian influenza virus (AIV)	Intravenous 1 × 105 cells/100 μl		∙ Post BM-MSC treatment, levels of inflammatory chemokines and cytokines reduced ∙ Increased expression of anti-inflammatory factors were observed	[55]
	Female Balb/C mice	H5N1 Influenza A virus	5 × 105 cells/100 μl		∙ Survival and body weight of treated mice was greater than the control mice ∙ Wet-to-dry lung weight ratio of ALI induced and treated mice were less ∙ MSC treatment induced alveolar M2 phenotype macrophages, overexpression of CFTR (cystic fibrosis transmembrane conductance regulator) protein expression	[56]
	C57BL/6 mice	Bleomycin injected into tracheal lumen	Intravenous 0.1 ml of 5 × 105 cells/ml BM-MSCs		∙ Suppression of inflammatory cytokines and increased expression of anti-inflammatory cytokines (IFN-γ, IL-2, IL-4, and IL-1 α) were observed	[180]
	C57BL/6 male mice	E. coli induction	1 × 106 cells/30 µl		∙ Neutrophile count and concentration of MIP-2 in BAL was reduced	[181]
	BALB/C female mice	LPS induction	Oral administration Two doses of 2.5 × 105/100 μl hBM-MSCs at 30 min interval		∙ Neutrophile count and MPO (Myeloperoxidase) important marker for neutrophile infiltration was reduced ∙ Reduction in the expression of MCP-1, IL-1α, RANTES, IL-1β, IP-10, IL-17, IL-6, MIP-1α and were observed ∙ Upregulation of anti-inflammatory cytokine TNF-α-induced protein 6 (TSG-6), IL-1RN, and regenerating protein keratinocyte growth factor (KGF)	[182]
	C57BL/6 male mice	E. coli LPS induction	Intratracheal 5 × 105/30 μl		∙ Significantly increased the LXA4 (lipoxin A4) level while reduced the production of TNF-α and MIP-2	[183]
	Sprague–Dawley male rats	Ventilator-induction	3 different routes of delivery ∙ Intratracheal ∙ Intraperitoneal ∙ Intravenous 4 different dosage ∙ 1 × 106 cells/kg ∙ 2 × 106 cells/kg ∙ 1 × 106 cells/kg ∙ 10 × 106 cells/kg		∙ Better results were shown by intravenous and intratracheal route ∙ Lowest effective dose of hBM-MSCs was 2 × 106 cells/kg ∙ Enhanced lung repair, restoring oxygenation, improved lung compliance, reduced alveolar edema, and restored lung architecture	[184]
	Kunming mouse	Hypoxia induction	Intraperitoneal 1 × 105 cells		∙ Decrease in genes associated with fibrosis (TGFβ1 (transforming growth factor β1), collagen1α and TIMP-1 (tissue inhibitor of metalloproteinases1) ∙ Expression levels of IL-1, TNFα was reduced	[185]
	Sheep	Cotton smoke insufflation followed by instillation of live Pseudomonas aeruginosa	Intravenous Lower dose—5 × 106 cells/kg Higher dose—10 × 106 cells/kg		∙ Oxygenation was improved in treated sheep	[186]
hBM-MSC and mBM-MSC	Wistar male rats	Severe blunt chest trauma by single blast wave centered on the thorax	Intravenous 5 × 106 cells/ml		∙ Lower level of cytokines IL-1β, IL-6 and chemokines CXCL1, CCL2 ∙ Higher levels of TNF-α in the BAL	[187]
mBM-MSCs	C57BL/6 male mice	E. coli endotoxin induction	– 7.5 × 105 cells/30 µl		∙ Reduced concentration of MIP-2 and TNF-α while concentration of IL-1ra, IL-10, and IL-13 were increased	[188]
	C57Bl/6 female mice	Elastase induction	Intravenous 1 × 106 cells		∙ Reduction of peripheral lung tissue damage was observed in combination therapy of mBM-MSC and ATRA (All-trans retinoic acid) ∙ Reduction in MLIs (mean linear intercepts) and increases in S (alveolar surface area) values	[189]
	Sprague–Dawley male rats	Ventilator induction	Intratracheal 4 × 106 cells/30 µl		∙ Improvement in lung microvascular permeability, decreasing, lung wet: dry weights and reduction in BAL protein concentrations ∙ Lung neutrophil, macrophages and inflammatory cytokines (TNF-α, IL-6) accumulation was reduced ∙ Increase in KGF levels	[190]
	C57BL/6 male mice	E. coli K1 induced	Intratracheal 7.5 × 105 cells/30 µl		∙ Upregulation of lipocalin 2 inhibiting the bacteria ∙ mBM-MSCs reduced early pro-inflammatory responses in BALF	[191]
	C57BL/6 mice	E. coli endotoxin induced	Intravenous 1 × 105 cells/0.05 ml		∙ Decrease in IL-6, IL-10, MCP-1, MIP-1α, KC, IP-10, IL-1β, and IFN-γ ∙ Induction of M2 type of macrophage	[192]
PDFGRa+ SCA1+ CD45− TER119− (PαS) expressed mBM-MSCs	C57BL/6 (C57BL/6NCrl) and B6.CgTg (TcraTcrb) 425Cbn/J mice	Klebsiella pneumoniae induced	Intratracheal ∙ × 106 cells		∙ Significantly reduced alveolitis and protein leakage, reduced alveolar TNF-α and IL-12p70 expression ∙ Decreased infiltration of respiratory DC cells	[193]
HGF (Hepatocyte growth factor) gene knockdown rBM-MSC and rBM-MSC	Sprague–Dawley male rats	LPS induction	Intravenous 5 × 106 cells/100 µl		∙ rBM-MSC decreased the lung wet weight: body weight ratio, inflammatory reactions while HGF knockdown rBM-MSC did not show these anti-inflammatory response	[194]
VEGF gene knockout rBM-MSCs	Sprague–Dawley rats	LPS induction	Intravenous 5 × 106 cells/100 µl		∙ VEGF knockdown rBM-MSCs showed higher wet weight: body weight ratio and less pulmonary vascular permeability ∙ VEGF knockdown rBM-MSCs also showed less beneficial in treating inflammatory responses than rBM-MSCs	[195]
Overexpressed ACE-2 gene in mBM-MSCs	C57BL/6 male mice	LPS induction	Intravenous 5 × 105 cells/100 µl		∙ Lung injury, vascular permeability, neutrophil counts, histopathological index in BALF declined ∙ Reduction in the expression levels of IL-1β, Ang-2, and IL-6 was observed ∙ IL-10 protein levels increased	[196]
hBM-MSCs hUC-MSCs and CD362+ hUC-MSCs at (3,5,7,10 passage numbers)	Sprague–Dawley male rats	E. coli induction	Intratracheal 1 × 107 cells		∙ Passage number above 3 did not have much efficacy ∙ CD362+ hUC-MSCs were effective in reducing lung injuries ∙ Cryopreserved stem cells also showed efficacy along with antibiotic therapy	[197]
mAD-MSCs	C57BL/6 male mice	Pseudomonas aeruginosa induced	Intratracheal Low dose 1 × 105 cells High dose 1 × 106 cells		∙ Inhibition of alveolar neutrophil accumulation, decreased levels of MPO, MIP-2 and total proteins in BALF ∙ Inhibited the overproduction of prostaglandin E2, improved phagocytosis	[198]
hCMSCs (human chorionic villi-derived MSCs)	C57BL/6 male mice	LPS induction	Intravenous 5 × 105 cells/200 µl		∙ Reduction in Glucagon-like peptide-1 receptor (GLP-1R), specific surfactant protein C (SPC), Angiopoietin-1(Ang-1), and Fibroblast growth factor-10 (FGF-10) levels ∙ Combination of hCMSCs with liraglutide showed more therapeutic efficacy	[199]