Abstract

The healthy adult lung is largely quiescent but can respond to injury and replace damaged or lost cells. However, the identities and origins of regenerative cell states remain poorly understood. Here we present the Human Developmental Lung Cell Atlas (HDLCA), a curated single-cell reference atlas of the respiratory system across the lifespan, integrating 253 datasets from 225 studies, and comprising over 18 million cells from 3,198 samples and 2,460 individuals across 34 anatomical locations in both health and disease. The HDLCA defines 142 consensus lung cell types, including 13 rare and 8 previously undescribed ones. Notably, we identify a rare intermediate alveolar epithelial progenitor (Int AP) population in normal lungs, with transcriptional signatures shared by alveolar type 2 (AT2) and alveolar type 1 (AT1) cells. Trajectory inference indicates that Int AP cells arise from both AT2 and SCGB1A1+ secretory cells and give rise to AT1 cells, with Hippo-YAP/TAZ signalling governing lineage specification. Int AP cells are associated with genetic susceptibility to idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, and their dysfunction may contribute to abnormal alveolar repair and regenerative failure in both diseases. The HDLCA provides a unified atlas-level reference for mapping respiratory cellular diversity, uncovering reparative cell dynamics and informing regenerative and cell-based therapeutic strategies.