Cdh16 expression marks the activated alveolar type 2 cells that contribute to alveologenesis and regeneration

Cadherin-16 (Cdh16) is transiently expressed during lung development, while its functional role remains unclear. Herein, we identified Cdh16 as a marker for a dynamic population of alveolar epithelial progenitors. Spatiotemporal and lineage tracing analysis in mice demonstrated that Cdh16-positive (Cdh16 Pos ) cells prevalent in distal buds during pesudoglandular stage, contributing to both AT2 and AT1 cell lineages, while its expression decreased subsequently and maintained a very low level postnatally. Single-cell RNA sequencing confirms that these cells represent a transient intermediate state during the differentiation from AT2 to AT1 cells. Functional ablation of the Cdh16 Pos lineage in vivo disrupts alveolar morphogenesis, impairing epithelial differentiation. Additionally, Cdh16 is both necessary and sufficient for alveolar progenitor differentiation and alveolar organoid maturation. In the adult lung, the quiescent Cdh16 Pos population is rapidly activated following lipopolysaccharide-induced injury, expands, and differentiates along the AT2-to-AT1 axis to contribute to alveolar repair. Depletion of this lineage compromises regeneration, leading to persistent structural defects. Our findings establish Cdh16 Pos cells as a crucial source of alveolar epithelial progenitors essential for lung development and injury-induced regeneration, our work indicate that Cdh16 is a key regulator of alveolar lineage specification.