Review of the potential of mesenchymal stem cells for the treatment of infectious diseases

Figure 4 Signaling pathways modified by mesenchymal stem cells in alveolar lung epithelial cells during lung injury. Mesenchymal stem cells (MSCs) reduce alveolar permeability and promote survival of alveolar epithelial cells through secretion of lipoxinA4 (LXA4), angiopoietin (Ang1), keratinocyte growth factor (KGF), along with extracellular vesicles (EVs). During acute lung injury (ALI), LXA4 inhibits apoptosis of alveolar epithelial cells by inhibiting caspase-3[104]. LXA4 also upregulates ion channels like Na⁺/K⁺ pump and rescues expression of cystic fibrosis transmembrane conductance regulator and epithelial Na⁺ channel by inhibiting Akt phosphorylation[96]. LXA4 also rescues E-cadherin expression by reducing reactive oxygen species via modulation of nuclear factor erythroid 2–related factor 2/heme oxygenase-1 expression[103]. LXA4, as well as Ang1, promote the expression of tight junction proteins like occludin, Zona occludens, and claudin 1[64,94,100]. Ang1 also rescues the expression of claudin 18 by inhibiting NF-κB. Ang1 upregulates Rac1, which promotes the formation of adherens and tight junctions[106]. KGF promotes the secretion of surfactant protein SP-A by alveolar epithelial cells and promotes the expression of Na⁺/K⁺ pump[87]. Inhibition of mTOR by miR-100 present in EVs secreted by MSCs increases autophagy, thereby promotes survival of epithelial cells during ALI. Ca²⁺ dependent transfer of mitochondria from MSCs, through gap junctions formed by Cx43, increases ATP generation in epithelial cells and improves their survival[112]. Akt: Protein kinase B; Ang1: Angiopoietin; AQP5: Aquaporin-5; ATP: Adenosine triphosphate; Cas3: Caspase-3; CFTR: Cystic fibrosis transmembrane conductance regulator; CLD1: Claudin 1; ENaC: Epithelial Na⁺ channel; EVs: Extracellular vesicles; HO-1: Heme oxygenase-1;KGF: Keratinocyte growth factor; LXA₄: LipoxinA4; MSC: Mesenchymal stem cell; mTOR: Mammalian target of rapamycin; NF-κB: Nuclear factor-kappa B; Nrf2: Nuclear factor erythroid 2-related factor 2; OCLD: Occludin; Rac1: Rac family small GTPase 1; RhoA: Ras homolog family member A; ROS: Reactive oxygen species; ZO-1: Zona occludens.