Abstract

Airway basal stem cells (BCs) are recognized as resident stem cells responsible for reconstituting epithelial barriers and differentiating into multiple epithelial cell types following severe lung injury. However, the mechanism that the injured lung microenvironment uses to modulate BC-mediated lung repair remains unclear. Here, we showed that the profibrotic transforming growth factor–β (TGF-β) gradient from the injured lung immune microenvironment can be sensed by BCs. Targeted degradation of Smad2/3 in human BCs via proteolysis targeting chimera (PROTAC) disrupted TGF-β signaling, causing cell hyperplasia and barrier function loss after being transplanted into the alveolar area. Genetic ablation of the TGF-β receptor or Smad4 in mouse BCs impaired multilineage differentiation and suppressed migration to the alveolar injury site. These data indicated that TGF-β signaling is essential for BC-mediated lung repair. Moreover, we genetically engineered human BCs to release antifibrotic bone morphogenetic protein 7 (BMP7) in response to microenvironmental TGF-β stimulation. Transplantation of this iBMP7-BC enhanced lung repair and reduced fibrosis. Collectively, this study delineates how TGF-β governs BC behavior and provides a microenvironment-responsive cell therapeutic strategy for pulmonary fibrosis.