Genomic, epigenomic, and biophysical cues controlling the emergence of the lung alveolus.

Zepp, Jarod A; Morley, Michael P; Loebel, Claudia; Kremp, Madison M; Chaudhry, Fatima N; Basil, Maria C; Leach, John P; Liberti, Derek C; Niethamer, Terren K; Ying, Yun; Jayachandran, Sowmya; Babu, Apoorva; Zhou, Su; Frank, David B; Burdick, Jason A; Morrisey, Edward E

The lung alveolus is the functional unit of the respiratory system required for gas exchange. During the transition to air breathing at birth, biophysical forces are thought to shape the emerging tissue niche. However, the intercellular signaling that drives these processes remains poorly understood. Applying a multimodal approach, we identified alveolar type 1 (AT1) epithelial cells as a distinct signaling hub. Lineage tracing demonstrates that AT1 progenitors align with receptive, force-exerting myofibroblasts in a spatial and temporal manner. Through single-cell chromatin accessibility and pathway expression (SCAPE) analysis, we demonstrate that AT1-restricted ligands are required for myofibroblasts and alveolar formation. These studies show that the alignment of cell fates, mediated by biophysical and AT1-derived paracrine signals, drives the extensive tissue remodeling required for postnatal respiration.