Deficiency of Aging-Related Gene Chitinase-Like 4 Impairs Olfactory Epithelium Homeostasis

Mammalian olfactory epithelium (OE) undergoes consistent self-renewal throughout life. In OE homeostasis, globose basal cells (GBCs) contribute to the generation of olfactory sensory neurons (OSNs) to replace old ones. Chitinase-like 4 (Chil4), a chitinase-like protein expressed in supporting cells, plays a critical role in OE regeneration, while its role in tissue homeostasis is still elusive. Here, we found that Chil4 is upregulated in the aged OE. Deletion of Chil4 leads to a reduction in the number of GBCs and immature OSNs (iOSNs). Chil4^-/- GBCs show attenuation in cell cycle progression and an aberrant expression pattern of cell-cycle-related genes such as Cdk1. Chil4 deletion causes loss of a specific subcluster of GAP43⁺ iOSNs expressing Cebpb, Nqo1 and low level of mature OSN (mOSN) marker Stoml3 (iOSN_CeSt^LNq), potentially suggesting a transitional state between immature and mature neurons. Chil4 knockout induces inflammatory activation in Iba1⁺ microglia (MG)-like cells in the OE. Chil4 downregulation in aged organoids reduced the number of mature sensory neurons, suggesting a necessary role of Chil4 in maintaining neuronal generation in the aged OE. Collectively, these observations reveal a previously unidentified function of Chil4, establishing the cellular mechanism underlying OE homeostasis.