Fig. 2

Schematic diagram of the mechanisms of action of MSCs in ARDS. MSCs act through the secretion of soluble factors and extracellular vesicles and the transfer of mitochondria. MSCs promote epithelial and endothelial repair, alveolar fluid clearance, and bacterial clearance and exert anti-inflammatory and antiapoptotic effects. MSCs release the peptide LL37 and inhibit neutrophil intravasation and NET formation, favoring bacterial clearance. In M1 macrophages, MSCs increase phagocytosis and promote bacterial clearance. MSCs activate regulatory T cells by inhibiting proliferation and activation. MSCs enhance the differentiation of macrophages to the M2 phenotype, produce anti-inflammatory cytokines, and inhibit the proinflammatory factors TNF-α, IL-6, and IL-1β, which is beneficial for tissue repair and may prevent the release of cytokine storms by the immune system. Simultaneously, Na+-K+-ATPase is upregulated in lung AT-II cells and inhibits fibrosis. By decoupling oxidative phosphorylation, MSCs reduce reactive oxygen species (ROS) levels and shift the metabolism to sugar metabolism, thereby promoting cell survival and reducing cell death. In addition, MSCs also promote the clearance of alveolar fluid by increasing the levels of fibroblast growth factor 7 (FGF7) and angiopoietin-1 (Ang-1). In addition to reducing the production of cytokine storms by the immune system, MSC therapy can also promote endogenous repair, restore the lung microenvironment of patients, protect alveolar epithelial cells, block pulmonary fibrosis, and treat COVID-19-associated pneumonia [26]. MSCs restored epithelial and endothelial permeability by releasing Ang-1. MSCs may promote the regeneration of type II alveolar epithelial cells by producing keratinocyte growth factor (KGF), vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF); prevent the apoptosis of endothelial cells; and contribute to the repair of the alveolar epithelial barrier in ARDS-associated injury to enhance the repair of injured lung tissue in COVID-19 patients with ARDS. Text in a red font color indicates COVID-19-associated effects. EV, extracellular vesicles; NETs, neutrophil extracellular traps; Treg, regulatory T cells; AT-II, alveolar type II; ROS, reactive oxygen species; FGF7, fibroblast growth factor 7; Ang-1, angiopoietin-1