An essential function for autocrine hedgehog signaling in epithelial proliferation and differentiation in the trachea

The tracheal epithelium is a primary target for pulmonary diseases as it provides a conduit for air flow between the environment and the lung lobes. The cellular and molecular mechanisms underlying airway epithelial cell proliferation and differentiation remain poorly understood. Hedgehog (HH) signaling orchestrates communication between epithelial and mesenchymal cells in the lung, where it modulates stromal cell proliferation, differentiation and signaling back to the epithelium. Here, we reveal a previously unreported autocrine function of HH signaling in airway epithelial cells. Epithelial cell depletion of the ligand sonic hedgehog (SHH) or its effector smoothened (SMO) causes defects in both epithelial cell proliferation and differentiation. In cultured primary human airway epithelial cells, HH signaling inhibition also hampers cell proliferation and differentiation. Epithelial HH function is mediated, at least in part, through transcriptional activation, as HH signaling inhibition leads to downregulation of cell type-specific transcription factor genes in both the mouse trachea and human airway epithelial cells. These results provide new insights into the role of HH signaling in epithelial cell proliferation and differentiation during airway development.

Automated summary

The tracheal epithelium is a crucial element in pulmonary diseases, and its understanding of cell proliferation and differentiation is limited. The Hedgehog (HH) signaling pathway plays a role in communication between epithelial and mesenchymal cells in the lung, affecting stromal cell proliferation, differentiation, and epithelial signaling. This study discovered an autocrine HH signaling function in airway epithelial cells, with its inhibition leading to defects in cell proliferation and differentiation. Additionally, HH function is mediated by transcriptional activation, as inhibition of HH signaling downregulates cell type-specific transcription factor genes in both mouse trachea and human airway epithelial cells. These findings provide new insights into the role of HH signaling in epithelial cell proliferation and differentiation during airway development.