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. Chil4 regulates horizontal basal cell activation, sensory neuronal and sustentacular cell differentiation, and inflammatory cell recruitment in the olfactory epithelium post injury, revealing a complex mechanism underlying olfactory epithelium regeneration.