3D organoid model reveals club cell differentiation toward alveolar lineage
Airway club cells serve as a critical progenitor population that responds to alveolar and airway injury, yet their plasticity remains incompletely characterized. Here, we demonstrate that club cells exhibit the capacity to differentiate into alveolar type 1 (AT1) cells and identify Notch3 signaling as a key suppressor of club-to-AT1 differentiation. Mechanistically, Notch3-mediated inhibition of club cell differentiation depends on YAP/TAZ activity regulation. We also found that club cell-derived AT1 differentiation contributes to epithelial barrier restoration following lung injury. Our work unveils the multifaceted plasticity of club cells and provides new insights into the interplay between lung regeneration and fibrosis.