Tuft cells shape airway remodeling by eliciting OXGR1- and SOX9-dependent stem cell programs

Tissue-resident stem cells play an essential role in repairing barrier tissues subjected to frequent insults. However, the local cues that coordinate successful barrier repair or lead to tissue remodeling are largely unknown. Here we use murine models of airway injury, fate mapping, and null strains to identify a role for rare tuft epithelial cells in signaling to submucosal stem cells through the generation of cysteinyl leukotrienes (CysLTs) and activation of the CysLT receptor OXGR1. This results in mobilization of SOX9⁺ submucosal gland progenitors, aberrant repair of the surface airway epithelium, and durable features of airway remodeling including submucosal gland hyperplasia and collagen deposition. Remarkably, selective deletion of SOX9 from the airway stem compartment allows epithelial restoration and prevents tissue remodeling. These findings demonstrate a tuft cell- OXGR1- and SOX9- circuit that remodels the airway after injury and is detected in the human sinus mucosa.