Airway epithelial progenitors regenerate the distal lung

Abstract

Background: The cellular source(s) for alveolar type II (ATII) renewal after lung injury remain(s) elusive. Both CCSP+ bronchial (Kumar, P.A. et al. Cell 2011;147:525-38) and LYZ2+ alveolar (Desai, T.J. et al. Nature 2014;507:190-4) progenitor cells were recently implicated in this process. Aim: To pin the lung stem cells that repopulate the alveoli after ATII cell death. Methods: Scgb1a1.Cre and Lyz2.Cre mice expressing Cre recombinase in different lung lineages were crossed to mT/mG Cre -reporter mice expressing GFP in Cre -recombined cells and tdTomato in all others. These lung cell fate reporters were treated with bleomycin or naphthalene for induction of ATII or bronchial epithelial cell death, respectively. Lungs were serially examined for GFP+ cells and CCSP/SFTPC expression before and after injury. Results: Scgb1a1.Cre;mT/mG offspring displayed complete and exclusive GFP labelling of airway, but not alveolar epithelium, while Lyz2.Cre;mT/mG youngsters exhibited GFP marking of ∼50% of ATII, but not of airway epithelial cells, providing two complementary models of airway versus alveolar cellfate. Aging Scgb1a1.Cre;mT/mG mice manifested spontaneous dispersion of GFP+ bronchial progenitors away from the airways into the distal alveoli, to subsequently express SFTPC and to replace naturally dying ATII cells, a process intensified by bleomycin-induced ATII death. Using both complementary lineage models, we also determined that airway, but not alveolar progenitors, repopulated the bronchi after naphthalene-triggered injury. Conclusions: Bronchial progenitors migrate into the alveoli and attain the ATII phenotype upon lung injury. Funding: European Research Council Starting Independent Investigator Grant #260524.