Wu Tingting, Li Weihao, Zhuang Liujing, Liu Jinxia, Wang Ping, Gu Ye, Liu Yongliang, Yu Yiqun
ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, Fudan University, Shanghai, China.
Olfactory Disorder Diagnosis and Treatment Center, Eye & ENT Hospital, Fudan University, Shanghai, China.
Cell Prolif. 2025 Aug;58(8):e70055. doi: 10.1111/cpr.70055. Epub 2025 May 19.
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_CeStNq), 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.
哺乳动物的嗅觉上皮（OE）在整个生命过程中持续进行自我更新。在OE的稳态中，球状基底细胞（GBCs）有助于生成嗅觉感觉神经元（OSNs）以替代衰老的神经元。几丁质酶样4（Chil4）是一种在支持细胞中表达的几丁质酶样蛋白，在OE再生中起关键作用，但其在组织稳态中的作用仍不清楚。在此，我们发现Chil4在衰老的OE中上调。Chil4的缺失导致GBCs和未成熟OSNs（iOSNs）数量减少。Chil4 GBCs在细胞周期进程中表现出减弱，以及细胞周期相关基因如Cdk1的异常表达模式。Chil4缺失导致表达Cebpb、Nqo1且成熟OSN（mOSN）标志物Stoml3水平较低的GAP43 iOSNs的一个特定亚群缺失（iOSN_CeStNq），这可能表明在未成熟和成熟神经元之间存在一种过渡状态。Chil4基因敲除诱导OE中Iba1小胶质细胞（MG）样细胞的炎症激活。在衰老类器官中Chil4下调减少了成熟感觉神经元的数量，表明Chil4在维持衰老OE中的神经元生成方面具有必要作用。总的来说，这些观察结果揭示了Chil4以前未被识别的功能，确立了OE稳态的细胞机制。
