Abstract
Somatic cell gene editing and orthotopic transplantation have the potential to correct lung sequelae in monogenic diseases, including Cystic Fibrosis. Within the pseudostratified airway epithelium, basal cells (BC) serve as stem cells and are thought to be the optimal therapeutic target. However, the airway contains transcriptionally distinct BC, and emerging data suggest that these subtypes are variants rather than discrete entities. Since this ambiguity impedes therapy development, we investigated human BC diversity in systems that are frequently used to produce and test BC therapeutics. Single cell cloning and transcriptomics supported a transitional state model in which long-lived BC exist in a continuum that includes multipotential cells and those that are progressing toward a cycling or secretory fate. Functional analyses demonstrated that the environment determined the distribution of cells along the continuum. This plasticity supports the conclusion that BC are a community of variants.