摘要：SummaryThe significance of alveolar epithelial type 2 (AT2) cell proliferation for lung alveolar epithelial homeostasis and regeneration after injury has been widely accepted. However, the heterogeneity of AT2 cell population for cell proliferation capacity remains disputed. By single-cell RNA sequencing and genetic lineage labeling using the Ki67 knock-in mouse model, we map all proliferative AT2 cells in homeostatic and regenerating murine lungs after injury induced byStreptococcus pneumoniaeinfection. The proliferative AT2 cell population displays a unique transcriptional program, which is regulated by activating transcription factor 3 (ATF3) and thyroid hormone receptor alpha (THRA) transcription factors. Overexpression of these two transcription factors in AT2 cells promoted AT2 cell proliferation and improved lung function after injury. These results indicate that increased expression of ATF3 and THRA at the onset of lung epithelial regeneration is required to permit rapid AT2 cell proliferation and hence progression through the recovery of lung epithelium.Graphical abstractDisplay OmittedHighlights•Alveolar epithelial type 2 (AT2) cells in mice are heterogeneous•ScRNA-seq identified a unique transcriptional program in proliferative AT2 cells•ATF3 and THRA factors exert proliferative functions in AT2 cellsCell biology; Stem cells research; Omics; Transcriptomics
