RNAseq transcriptomic comparison of mouse tracheal pseudostratified vs hillock basal stem cells

Airway hillocks are stratified epithelial structures of unknown function. We show that the luminal cells of hillocks are squamous barrier cells that shield a unique population of underlying hillock basal stem cells. Hillocks occur in characteristic locations and persist for months in uninjured mice. Following injury, hillock basal stem cells undergo massive clonal expansion, resurface denuded airway, and demonstrate extreme plasticity, generating classic airway epithelium with its six component cell types. Remarkably, hillocks resist a very broad spectrum of injuries, including toxins, infection, acid, and physical injury. Furthermore, hillock basal stem cells are characterized by enhanced expression associated with barrier function, cell adhesion, and retinoic acid catabolism. Indeed, hillock basal cells preferentially expand, stratify, and keratinize in the setting of retinoic acid signaling inhibition, a known clinical cause of squamous metaplasia. Finally, we identify human hillocks whose basal cells demonstrate preferential sensitivity to retinoic acid inhibition and conserved barrier properties. Given their capacity for clonal expansion, their plasticity, and their retinoic acid sensitivity, the existence of hillocks and hillock basal stem cells have broad implications for injury repair and for defining the origin of squamous metaplasia, long thought to be a precursor of lung cancer.