Hippo signaling differentially regulates distal progenitor subpopulations and their transitional states to construct the mammalian lungs

Lung size control and cell type specification are key unresolved issues. In this study, we have engineered mosaic patterns of Hippo signaling to reveal the developmental potential of SOX9 ⁺ progenitors at the distal lung buds. Our results show that the distal SOX9 ⁺ subdomain is sufficient to direct lung outgrowth through bifurcation, providing a mechanism for lung size control. Through single-cell analyses, we identify transitional cell states and candidates for promoting cell fates. Moreover, genetic analysis reveals that Hippo signaling induces distinct cell fates at different SOX9 ⁺ subdomains to produce the conducting airways and the alveolar epithelium. These results provide the first map of the developmental paths of lung cells. Some of the developmental paths of transitional cell states in mice correspond to those in human lungs. Together, these studies provide mechanistic insight into how Hippo signaling controls the sequential expansion and differentiation of SOX9 ⁺ progenitors to construct the mammalian lungs.