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

• DOI: 10.1242/dev.199804
• Publication Date: 2022-02-03T08:11:49Z
• Authors: Wenguang Yin; Andreas Liontos; Janine Koepke; Maroua Ghoul; Luciana Mazzocchi; Xinyuan Liu; Chunyan Lu; Haoyu Wu; Athanasios Fysiko...; Alexandros Sounto...; Werner Seeger; Clemens Ruppert; Andreas Günther; Didier Y. R. Stai...; Christos Samakovlis
• Keywords: Mice, Knockout; 0301 basic medicine; 0303 health sciences; Down-Regulation; Cell Differentiation; Epithelial Cells; Embryo, Mammalian; Smoothened Receptor; Trachea; Autocrine Communication; Mice; 03 medical and health sciences; Animals; Humans; Hedgehog Proteins; Lung; Cells, Cultured; Research Article; Cell Proliferation; Signal Transduction; Transcription Factors

ABSTRACT 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.