Bronchioalveolar stem cells are a main source for regeneration of distal lung epithelia

Bronchioalveolar stem cells (BASCs) are a potential source for lung regeneration, but direct in vivo evidence is critically missing since specific genetic labeling of BASCs has not been possible. We developed a novel cell tracing approach based on intein-mediated assembly of newly engineered split-effectors, allowing selective targeting of dual-marker expressing BASCs. We found that BASCs generate the majority of distal lung airway cells after bronchioalveolar damage but only moderately contribute to cellular turnover under homeostatic conditions. Importantly, DTA-mediated ablation of BASCs compromised proper regeneration of distal airways. The study defines BASCs as crucial components of the lung repair machinery and provides a paradigmatic example for the detection and manipulation of stem cells that cannot be recognized by a single marker alone. Overall design: Bulk RNAseq of FACS-isolated lung epithelial cell types (BASC/AT2/Club) in duplicates.