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_CeStLNq), 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.