Chil4 regulates basal cell activation and neuronal differentiation in olfactory epithelium regeneration

The mammalian olfactory epithelium (OE) exhibits remarkable capacity for continuous regeneration. Our previous work demonstrated that Chitinase-like 4 (Chil4) regulated regeneration in the injured OE. Expanding upon these findings, here we reported that Chil4 deficiency resulted in zone-specific attenuation of neuronal regeneration, increased population of globose basal cells (GBCs), delayed horizontal basal cell (HBC) activation post injury, and enhanced recruitment of CD45+ inflammatory cells to the regenerating OE.

Moreover, scRNA-seq data support that DNA replication and cell cycle-related genes were upregulated in Krt6a+ activated HBCs, and Cd6-Alcam pair contributed to cell cycle progression of activated HBCs in the Chil4−/− OE by Cd4+ T cells. The biased sustentacular cell regeneration induced by Chil4 deletion was mediated by Notch-Hes1 signaling, and γ-secretase inhibitor LY411575 enhanced neuronal differentiation and inhibited sustentacular cell regeneration in the Chil4−/− OE. Collectively, this study elucidates critical events underlying the Chil4 deficiency in OE regeneration.

These findings provide insights into the complex molecular mechanisms governing olfactory epithelium regeneration. This study was funded by National Natural Science Foundation of China Grants (32271044, 82571283 to Y.Y.); Science and Technology Commission of Shanghai Municipality (23ZR1409600 to Y.Y.); Shanghai Municipal Education Commission, the Shanghai Oriental Scholar Program (GZ2022006 to Y.Y.); Shanghai Municipal Health Commission (GWVI-11.2-XD09 to Y.Y.); Fudan University, Shanghai Medical College, Young investigator for clinical and scientific research team (to Y.Y.). The scRNA-Seq data analysis was supported by the Medical Science Data Center of Fudan University.

We thank the staff members of the Integrated Laser Microscopy System at the National Facility for Protein Science in Shanghai (NFPS) for confocal data collection. These authors contributed equally: Tingting Wu, Weihao Li, Xuewen Li. ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China Tingting Wu, Weihao Li, Xuewen Li, Jinxia Liu & Yiqun Yu Olfactory Disorder Diagnosis and Treatment Center, Eye & ENT Hospital, Fudan University, Shanghai, China Key Laboratory of Animal Biodiversity Conservation and Integrated Pest Management, Chinese Academy of Sciences, Beijing, China University of Chinese Academy of Sciences, Beijing, China Correspondence to Yunfeng Zhang or Yiqun Yu.

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