Alveolar regeneration by airway secretory-cell-derived p63 progenitors.

Lung injury activates epithelial stem or progenitor cells for alveolar repair and regeneration. Unraveling the origin and fate of injury-induced progenitors is crucial for elucidating lung repair mechanisms. Here, we report that p63-expressing progenitors emerge upon bleomycin-induced mouse lung injury. Single-cell RNA sequencing and clonal analysis reveal that these p63 progenitors proliferate rapidly and differentiate into alveolar type 1 and type 2 cells through different trajectories. Dual recombinase-mediated sequential genetic-lineage tracing demonstrates that p63 progenitors originate from airway secretory cells and subsequently generate alveolar cells. Functionally, p63 activation is essential for efficient alveolar regeneration from secretory cells post injury. Our study identifies secretory-cell-derived p63 progenitors as contributors to alveolar repair, suggesting a potential therapeutic avenue for lung regeneration following injury.