Alveolar stem cells transdifferentiate to drive bronchiolar regeneration

The lung consists of two anatomically distinct compartments: the airways and the alveoli. Although airway epithelial stem cells are known to mobilize for alveolar regeneration, whether alveolar cells can reciprocally traverse these anatomical boundaries and contribute to bronchial repair remains unclear1–4. Here we developed dual-recombinase-mediated lineage-tracing techniques in mice to demonstrate that alveolar type 2 (AT2) cells migrate into injured bronchioles and transdifferentiate into club cells and ciliated cells, thereby actively contributing to airway regeneration. Mechanistically, after bronchial injury, infiltrating immune cells secrete SPP1, establishing a chemotactic gradient directing cell migration. Peribronchiolar AT2 cells sense this SPP1 signal through the integrin ITGB1 and migrate towards the injured bronchioles. On arrival, these migrated AT2 cells receive Notch ligands from resident ciliated cells, leading to Notch pathway activation, which in turn drives their transdifferentiation into club cells. This transdifferentiation process is accompanied by an intermediate stage marked by Cldn4 expression. Functional blockade of either SPP1 or ITGB1 impairs AT2 cell migration, whereas inhibition of Notch signalling prevents their transdifferentiation into club cells. Collectively, our findings reveal a cross-compartmental cellular mechanism for bronchiolar epithelial repair, expanding the current understanding of lung regenerative plasticity and potentially informing therapeutic strategies for airway injury. Identification of a cross-compartmental cellular mechanism for bronchiolar epithelial repair informs therapeutic strategies for airway injury.