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. [Display omitted] •p63+ progenitors emerge upon bleomycin-induced lung injury•p63+ progenitors differentiate into alveolar type 1 and 2 cells after injury•p63+ progenitors originate from airway secretory cells•p63 activation is essential for efficient alveolar regeneration from secretory cells Using genetic-lineage tracing and scRNA-seq, Lv et al. find that p63+ progenitors emerge after bleomycin-induced lung injury and differentiate into alveolar type 1 and 2 cells during lung repair. These p63+ progenitors originate from airway secretory cells, and their contribution to alveolar repair requires p63 activation.