Airway secretory cell-derived p63⁺progenitors contribute to alveolar regeneration after sterile lung injury

Abstract

Lung injury activates epithelial stem or progenitor cells for alveolar repair and regeneration. However, the origin and fate of injury-induced progenitors are poorly defined. Here, we report that p63-expressing progenitors emerge upon bleomycin-induced lung injury. These p63+ progenitors proliferate rapidly and differentiate into alveolar type 1 (AT1) and type 2 (AT2) cells through distinct trajectories. Dual recombinase-mediated sequential genetic lineage tracing reveals that p63+ progenitors originate from airway secretory cells and subsequently generate alveolar cells. Functionally, p63 activation is required for efficient alveolar regeneration from secretory cells. Our study identifies a secretory cell-derived p63+ progenitor that contributes to alveolar repair, indicating a potential therapeutic avenue for lung regeneration after injury.

Identifying a Lung Stem Cell Subpopulation by Combining Single-Cell Morphometrics, Organoid Culture, and Transcriptomics

“…The functions of p63 in alveolar regeneration were reported and were under discussion. 41 , 42 Our finding might indicate that p63 expression in airway epithelial cells reflects the intermediated state of transdifferentiation into alveolar epithelial cells. In humans, MUC5B upregulation caused by the single-nucleotide polymorphism on the promoter region is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis.…”