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Fig. 1 | Stem Cell Research & Therapy

Fig. 1

From: Human placenta-derived amniotic epithelial cells as a new therapeutic hope for COVID-19-associated acute respiratory distress syndrome (ARDS) and systemic inflammation

Fig. 1

Proposed therapeutic mechanisms of hAECs in COVID-19. (1) SARS-CoV-2 enters the respiratory system and attaches to ACE2 receptors located on the basolateral membrane of type II alveolar cells. ACE2 damage would result in AT1 accumulation in alveoli that could induce vasoconstriction, inflammation, fibrosis, and apoptosis of alveolar epithelial cells. (2) Interferons, especially type I, are released from infected type II alveolar cells that defend against the invading virus. (3.1) M1 macrophages are activated in the immune response process that release IL-1, IL-6, IL-8, TNF-alpha, G-CSF-alpha, MCP, IL-17, and IL-5. These factors activate the CD4+, CD8+, and Th17 T cells. (3.2) MDC, IL-5, and TNF-alpha have chemotaxis effects that cause the migration of leukocytes to the alveolar space. (3.3) IL-1β secreted by M1 macrophages could activate the hAECs. (4) Activated CD4+, CD8+, Th17 cause inflammation and cytokine storm that damage the endothelial and epithelial cells and alveolar fluid accumulation. T cells also have chemotaxis properties that can call the hAECs to the alveolar space. (5.1) hAECs release PGE-2, IL-10, and MIF that inhibit the activation of macrophages, CD4+, CD8+, and Th17 cells and modulate cytokine-producing inflammatory cells. (5.2) hAECs induce inhibitory cytokine production in T -helper 2 through IL-5 signaling cascade. (5.3) hAECs can be differentiated into alveolar cells that regenerate damaged lung tissue. (5.4) hAECs secrete AMPs such as HBD1, HBD2, HBD3, secretory leukocyte protease inhibitor, and elafin. AMPs play an essential role in the early immune response that reduces the spread of the virus. Furthermore, they have antimicrobial properties that prevent nosocomial infection. (5.5) HLA-G presented by hAECs can regulate the differentiation of Treg cells, preventing hyperinflammatory responses. This feature also reduces the chance of immune rejection in the human body. (5.6) Activated hAECs release some exosomes which contain regenerative agents and PI3K‐Akt pathway activators that induce M1 to M2 macrophage polarization. (5.7) hAECs release surfactants and TIMP that prevent the accumulation of the fluid in the alveoli. (6) hAECs secrete two types of glycosaminoglycans, perlecan and hyaluronic acid, that inhibit thrombosis. Thus, hAECs could play an important role as an inhibitor of clot formation in coagulation dysregulation caused by COVID-19. Abbreviations: hAECs, human amnion epithelial cells; ACE, angiotensin-converting enzyme; AT1, angiotensin 1; IL, interleukin; G-CSF, granulocyte colony-stimulating factor; MCP, monocyte chemoattractant protein; MDC, macrophage-derived chemokine; PGE, prostaglandin; MIF, macrophage migration inhibitory factor; AMPs, antimicrobial peptides; HBD, human beta-defensin; HLA, human leukocyte antigen; TIMP, inhibitor of metalloproteinase

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