Single cell RNAseq reveals a critical role of chloride channels in airway development

The conducting airway for air passage forms a protective mucosal barrier, and presents the primary target of various airway disorders. To better understand how the airway developmental programs are established to support air breathing and the barrier functions in newborns, we constructed a single-cell atlas of the human and mouse developing airway. Our data reveals hitherto unrecognized heterogeneity of cell states with distinct differentiation programs and immune features associated with the airway epithelium. It also reveals ubiquitous expression of both CFTR and Ano1/TMEM16A chloride channels in airway epithelium early in development. Genetic inactivation of TMEM16A in mice alters the epithelial cell landscape and results in multiple airway defects commonly observed in young cystic fibrosis patients with deficient CFTR activity. Together, our study illuminates unique programs for mammalian airway development and implicates chloride homeostasis as a key player in regulating epithelial barrier formation and function relevant to early onset airway diseases.