Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, United States.
Department of Biomedical Sciences, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, United States.
Stem Cell Res. 2020 Dec;49:102061. doi: 10.1016/j.scr.2020.102061. Epub 2020 Oct 23.
Constant neuroregeneration in adult olfactory epithelium maintains olfactory function by basal stem cell proliferation and differentiation to replace lost olfactory sensory neurons (OSNs). Understanding the mechanisms regulating this process could reveal potential therapeutic targets for stimulating adult olfactory neurogenesis under pathological conditions and aging. Ciliary neurotrophic factor (CNTF) in astrocytes promotes forebrain neurogenesis but its function in the olfactory system is unknown. Here, we show in mouse olfactory epithelium that CNTF is expressed in horizontal basal cells, olfactory ensheathing cells (OECs) and a small subpopulation of OSNs. CNTF receptor alpha was expressed in Mash1-positive globose basal cells (GBCs) and OECs. Thus, CNTF may affect GBCs in a paracrine manner. CNTF-/- mice did not display altered GBC proliferation or olfactory function, suggesting that CNTF is not involved in basal olfactory renewal or that they developed compensatory mechanisms. Therefore, we tested the effect of increased CNTF in wild type mice. Intranasal instillation of a focal adhesion kinase (FAK) inhibitor, FAK14, upregulated CNTF expression. FAK14 also promoted GBC proliferation, neuronal differentiation and basal stem cell self-renewal but had no effective in CNTF-/- mice, suggesting that FAK inhibition promotes olfactory neuroregeneration through CNTF, making them potential targets to treat sensorineural anosmia due to OSN loss.
成年嗅上皮中的持续神经发生通过基底干细胞的增殖和分化来维持嗅觉功能，以替代丧失的嗅觉感觉神经元 (OSN)。了解调节这一过程的机制可以揭示在病理条件和衰老下刺激成年嗅觉神经发生的潜在治疗靶点。星形胶质细胞中的睫状神经营养因子 (CNTF) 促进前脑神经发生，但它在嗅觉系统中的功能尚不清楚。在这里，我们在小鼠嗅上皮中表明 CNTF 表达于水平基底细胞、嗅鞘细胞 (OEC) 和一小部分 OSN 中。CNTF 受体 alpha 表达于 Mash1 阳性的球状基底细胞 (GBC) 和 OEC 中。因此，CNTF 可能以旁分泌的方式影响 GBC。CNTF-/- 小鼠没有显示出 GBC 增殖或嗅觉功能的改变，这表明 CNTF 不参与基底嗅觉更新，或者它们已经发展出补偿机制。因此，我们在野生型小鼠中测试了增加 CNTF 的效果。鼻内滴注粘着斑激酶 (FAK) 抑制剂 FAK14 可上调 CNTF 表达。FAK14 还促进了 GBC 增殖、神经元分化和基底干细胞自我更新，但在 CNTF-/- 小鼠中没有效果，这表明 FAK 抑制通过 CNTF 促进嗅觉神经再生，使它们成为治疗因 OSN 丧失导致的感觉神经性嗅觉丧失的潜在靶点。
