Regeneration of alveolar epithelium after injury. (A) Bleomycin-mediated injury results in widespread destruction of all alveolar epithelial cells. Surviving ATII cells are activated following injury, undergo proliferation and restore the alveolar epithelium. The regenerative process after bleomycin injury is associated with the progressive invasion of myofibroblasts, which form fibrotic foci featuring increased extracellular matrix deposition. Several sources for myofibroblasts have been proposed, including epithelial cells, circulating fibroblasts as well as resident (lipo)fibroblasts. Additional distal progenitor cell populations appear to contribute to the regeneration of alveolar epithelium, including Itgα6β4+ cells, Scgb1a1+ cells and distal airway stem cells (DASCs). The latter have basal cell characteristics, most likely originate from distal airway club stem cells and give rise to bronchiolar and alveolar epithelium. Colored cell outlines represent lineage trace markers. (B) Lineage relationships of alveolar epithelial stem cells and their differentiated progeny during regeneration of the alveolar epithelium after bleomycin injury. Dashed arrows represent lineage relationships, which are likely to occur but have not yet been definitively established. (C) Model highlighting molecular crosstalk between distal airway club stem cells and components of their niche, including airway smooth muscle and endothelium. For details see main text. BASC, bronchioalveolar stem cell.