A multipotent mouse distal airway secretory cell population that contributes to both airway and alveolar regeneration

The distal airway is a spatially distinct compartment whose contribution to lung repair remains poorly defined. We have identified an epithelial cell population enriched in the most distal airways of the mouse lung, that is not present in the alveolar epithelium. Using lineage tracing tools based on Cldn10 expression which marks these cells, we show that the Cldn10+ lineage in homeostatic conditions marks distal airway secretory cells in a highly specific manner, with only a small contribution to multi-ciliated cells and no contribution towards the basal stem cell lineage. Remarkably, these Cldn10+ distal secretory cells proliferate and display a high degree of multi-potency across the lung epithelial axis after injury, generating basal cells, multi-ciliated cells, and alveolar epithelium. In severely remodeled regions after injury, we show that Cldn10 lineage-labeled cells migrate from the airways and differentiate into alveolar epithelial cells. These findings establish the Cldn10 lineage that defines a distal airway secretory facultative progenitor with both intrapulmonary airway and alveolar potential, providing a genetic system for studying distal lung repair.