Function of epithelial stem cell in the repair of alveolar injury

Abstract

Alveoli are the functional units of blood-gas exchange in the lung and thus are constantly exposed to outside environments and frequently encounter pathogens, particles and other harmful substances. For example, the alveolar epithelium is one of the primary targets of the SARS-CoV-2 virus that causes COVID-19 lung disease. Therefore, it is essential to understand the cellular and molecular mechanisms by which the integrity of alveoli epithelial barrier is maintained. Alveolar epithelium comprises two cell types: alveolar type I cells (AT1) and alveolar type II cells (AT2). AT2s have been shown to function as tissue stem cells that repair the injured alveoli epithelium. Recent studies indicate that AT1s and subgroups of proximal airway epithelial cells can also participate alveolar repair process through their intrinsic plasticity. This review discussed the potential mechanisms that drive the reparative behaviors of AT2, AT1 and some proximal cells in responses to injury and how an abnormal repair contributes to some pathological conditions.

Glycogen Synthase Kinase-3 Inhibition by CHIR99021 Promotes Alveolar Epithelial Cell Proliferation and Lung Regeneration in the Lipopolysaccharide-Induced Acute Lung Injury Mouse Model

“…Moreover, several signaling pathways promoting the transition of AECII to AECI have been elucidated. Recent characterisation of AECII-derived intermediate cells, emerging during reparative stages after bacteria-induced damage, identified distinct AECII subgroups, supporting the hypothesis of AECII differentiation towards AECI [86]. This intermediate state was characterised by the expression of keratin (Krt) 8, Cldn4, Ctgf, and Sfn [86].…”

“…Recent characterisation of AECII-derived intermediate cells, emerging during reparative stages after bacteria-induced damage, identified distinct AECII subgroups, supporting the hypothesis of AECII differentiation towards AECI [86]. This intermediate state was characterised by the expression of keratin (Krt) 8, Cldn4, Ctgf, and Sfn [86]. Studies have suggested the involvement of immune cells and inflammatory paracrine factors such as TNF-α and IL-1β in ACEII repair and transition into AECI [87,88].…”

“…Our findings pave the way for novel therapeutic developments in lung injury, showing the use of GSK-3α/β inhibitors as a promising therapeutic strategy, notably in late-stage ARDS, when no effective treatment is available. Furthermore, in light of the AEC damage induced by SARS-CoV-2, the viral pathogen responsible for COVID-19 [86], the shared mechanisms observed in COVID-19-associated ARDS such as pronounced inflammation, lung injury, severe pulmonary edema, and epithelial repair [98,99], along with the existing scientific evidence highlighting the involvement of GSK-3 in the disease's development, this study has the potential to open up new possibilities for utilising GSK-3 inhibition with CHIR99021 in COVID-19 patients.…”

P21 facilitates macrophage chemotaxis by promoting CCL7 in the lung epithelial cell lines treated with radiation and bleomycin

“…During the period of lung fibrosis, several intermediate AECII was detected by specific markers such as keratin 8 (KRT8), claudin 4 (CLDN4) and stratifin (SFN). When the alveolar repair failed due to repetitive injury, the progression of chronic lung diseases could be triggered [ 40 ]. It was demonstrated that radiation-induced AECII senescence participated in pulmonary fibrosis, and NADPH oxidase (NOX) and insulin-like growth factor-1 receptor (IGF-1R) were significantly involved in [ 41 , 42 ].…”

Lung regeneration: diverse cell types and the therapeutic potential

“…20 Diverse in vivo injury models of mice and in vitro 3D organoid culture models have revealed the transient AT2 cell subpopulations that appear in the middle of the transition from AT2 to AT1, named as "alveolar differentiation intermediate (ADI)," "pre-alveolar type-1 transitional cell state (PATS)," "damage-associated transitional progenitors (DATPs)," or "AT0" by different groups. 19,[21][22][23] The expression profiles of these cells are somewhat similar; for example, most of them express keratin 8 (Krt8), while some also express claudin 4 (Cldn4), keratin 19 (Krt19), connective tissue growth factor (Ctgf), and stratifin (Sfn). 22 AT2 cells in regenerating lung models transiently acquire an intermediate state from which they can differentiate into AT1 cells or terminal and respiratory bronchiole secretory cells.…”