TABLE 3.

Therapeutic potential of EVs derived from mesenchymal stem cells in ARDS.

In vitro models
Model	EVs source	Main effects	References
Human macrophages stimulated with LPS or BALF from ARDS patients	Human BM-MSC	Decrease in inflammatory cytokines secretion and increase in M2 macrophage markers, IL-10 secretion and phagocytic capacity.	Zhu et al., 2014; Monsel et al., 2015; Morrison et al., 2017; Tang et al., 2017
Human endothelial cells stimulated with LPS, cytokines or plasma from ARDS patients	Human/mice BM-MSC	Increase in proliferation and IL-10 levels. Reduction in pulmonary capillary permeability, apoptosis, mitochondrial dysfunction and secretion of inflammatory cytokines and Ang-1 (EV cargo: HGF and mitochondria).	Tang et al., 2017; Wang et al., 2017; Hu et al., 2018; Dutra Silva et al., 2021
Human alveolar epithelial type 2 cells stimulated with LPS, cytokines or plasma from ARDS patients	Human BM-MSC	Decrease in protein permeability, inflammatory cytokines and Ang-1 secretion and mitochondrial dysfunction (EV cargo: mitochondria).	Monsel et al., 2015; Morrison et al., 2017; Dutra Silva et al., 2021
Human alveolar epithelial type 2 cells stimulated with Influenza virus	Swine BM-MSC	Reduction in replication and apoptosis.	Khatri et al., 2018
Ex vivo perfused human lungs rejected for transplantation	Human BM-MSC	Increase in alveolar fluid clearance and airway and hemodynamic parameters. Decrease in lung weight gain.	Gennai et al., 2015
Ex vivo perfused human lungs injured with severe E. coli pneumonia	Human BM-MSC	Increase in alveolar fluid clearance. Decrease in bacterial count, absolute neutrophil count and protein permeability.	Park et al., 2019
Ex vivo cultured human precision cut lung slices	Human BM-MSC	Attenuation of mitochondrial dysfunction and downregulation of TNF-α, IL-8 and RAGE (EV cargo: mitochondria).	Dutra Silva et al., 2021
In vivo models
Model	EVs source	Main effects	References
Endotoxin-induced ALI in mice	Human BM-MSC	Improvement in lung mitochondrial bioenergetics and decrease in BALF total protein and cell count.	Dutra Silva et al., 2021
		Reduction in the extravascular lung water and total protein levels in BALF, demonstrating a reduction in pulmonary edema and lung protein permeability. MVs also reduced the influx of neutrophils and macrophage inflammatory protein-2 levels in the BAL fluid (EV cargo: KGF mRNA).	Zhu et al., 2014
		Reduction in the influx of inflammatory cells in the injured alveoli, MIP-2 and albumin levels in BALF, pulmonary capillary permeability and histological injury (EV cargo: Ang-1 mRNA).	Tang et al., 2017
		Decrease in alveolar leukocytosis and protein leak, mitochondrial dysfunction and mortality and increase in surfactant secretion (EV cargo: mitochondria).	Islam et al., 2012
		Improvement in survival and decrease in histological severity, influx of inflammatory cells, cytokines, protein and bacteria (EV cargo: KGF).	Monsel et al., 2015
Hyperoxia-induced ALI in mice	Human UCB-MSC	Attenuation of impaired alveolarization and angiogenesis, increased cell death. Diminishment of activated macrophages and inflammatory cytokines secretion (EV cargo: VEGF).	Ahn et al., 2018
Haemorrhagic shock-induced ALI in mice	Human BM-MSC	Significant decrease in lung vascular permeability (via decreased activation of the cytoskeletal GTPase RhoA).	Potter et al., 2018
Traumatic-induced (weight-drop method) ALI in rats	Rat BM-MSC	Increase in survival and IL-10 level and decrease in oxidative stress, cell count, inflammatory cytokines secretion and protein in BALF (EV cargo: mitochondria).	Li Q.C. et al., 2019
Influenza virus-induced ALI in pigs	Swine BM-MSC	Reduction in infiltration of inflammatory cells to the lungs, thickening of alveolar walls and number of collapsed alveoli.	Khatri et al., 2018

ALI, acute lung injury; Ang-1, angiopoetin-1; ARDS, acute respiratory distress syndrome; BALF, bronchoalveolar lavage fluid; BM-MSC, bone marrow-derived mesenchymal stem cells; EV, extracellular vesicles; HGF, hepatocyte growth factor; IL, interleukin; KGF, keratinocyte growth factor; LPS, lipopolysaccharide; RAGE, receptor for advanced glyc end products; TNF-α, tumor necrosis factor α; VEGF, vascular endothelial growth factor.