Myoepithelial Cells of Submucosal Glands Can Function as Reserve Stem Cells to Regenerate Airways after Injury

Summary Cells demonstrate plasticity following injury, but the extent of this phenomenon and the cellular mechanisms involved remain underexplored. Using single-cell RNA sequencing (scRNA-seq) and lineage tracing, we uncover that myoepithelial cells(MECs) of the submucosal glands(SMGs) proliferate and migrate to repopulatethe airwaysurface epithelium (SE) in multiple injury models. Specifically, SMG-derived cells display multipotency and contribute to basal and luminal cell types of the SMGs and SE. Ex vivo expanded MECs have the potential to repopulateand differentiate into SE cells when grafted onto denuded airwayscaffolds. Significantly, we find that SMG-like cells appear on the SE of both extra- and intra-lobular airwaysof large animal lungs following severe injury. We find that the transcription factor SOX9is necessary for MEC plasticity in airwayregeneration. Because SMGs are abundant and present deep within airways, they may serve as a reserve cell source for enhancing human airwayregeneration.