We identified a previously uncharacterized progenitor population in distal airway, named lineage-negative epithelial progenitors (LNEPs), which exhibit a binary response to reconstitute epithelial barriers: differentiating into Krt5pos basal-like cell or alveolar type II cells (AEC2s). Local lung hypoxia, via hypoxia inducible factor (HIF)1a, drives Notch signaling and Krt5pos basal-like cell expansion in mice and humans upon major lung injury, resulting in aberrant alveolar repair. Activated murine Krt5pos LNEPs and hypoxic human AEC2s up-regulate strikingly similar core pathways underlying migration and squamous metaplasia. Increasing Wnt/beta-catenin activity in LNEPs attenuates Notch and Krt5 activation, favoring AEC2 differentiation. These findings implicate local lung hypoxia as a critical regulator of epithelial progenitors in response to lung injury and elucidate critical determinants of epithelial fate decisions governing the quality of alveolar repair.
Figure 1. The alveolar repair pathways.