Stem cell CNTF promotes olfactory epithelial neuroregeneration and functional recovery following injury.

Abstract

Olfactory sensory neurons (OSNs) in the olfactory epithelium (OE) are continuously replaced by neuroregeneration from basal stem cells. Acute inflammation destroys OSNs, causing hyposmia or anosmia, but leaves the basal stem cells intact. We previously found that ciliary neurotrophic factor (CNTF) is highly expressed in horizontal basal cells (HBCs) and the CNTF receptor is in globose basal cells (GBCs), which are the actively dividing cells that normally replace dying OSNs. Here, we investigated the role of CNTF in basal stem cell proliferation/differentiation and smell function recovery following methimazole-induced acute inflammatory OE injury. Methimazole increased inflammatory markers, TNFα, IL-6, and CD45, and depleted OSNs in the OE at 3 and 5 days. Simultaneously, CNTF and the GBC marker Mash1 were upregulated, suggesting that HBCs produced more CNTF, as validated using primary HBC cultures, to promote GBC proliferation. Methimazole increased GBC proliferation, as shown by the number of BrdU-labeled GBCs in CNTF+/+, but not in CNTF-/- littermate mice. Also, CNTF+/+ mice had higher levels of neuroregeneration and better smell function recovery than CNTF-/- littermates. This indicates that CNTF promotes GBC proliferation and promotes OE neuroregeneration and smell functional recovery. This study identifies the regenerative role of CNTF in HBCs and reveals the therapeutic potential to target CNTF signaling to improve olfactory neuroregeneration and functional recovery following injury.