The gene expression profiles of SOX9+ basal cells (BCs) compared to basal cells during the ALT injury/regeneration process in the surface airway epithelium (SAE).

Tissue-resident stem cells are crucial for repairing barrier tissues that experience frequent damage. However, the local signals that regulate this repair process remain largely unidentified. Here, we show that tuft cell-dependent CysLT activate the LTE4 receptor OXGR1 on SOX9+ accessory stem cells in submucosal glands (SMGs). Activated SMG progenitors regenerate the stem compartment of the SAE, but they also introduce a pro-inflammatory and mesenchymal program, leading to reduced differentiation of ciliated cells. This results in ineffective epithelial repair, causing epithelial injury and inflammation. These findings highlight a significant connection between tuft cell sensing of tissue damage and the onset of abnormal wound healing processes observed in the human airway.