Wnt-Notch信号通路共调控促进内耳毛细胞再生及其作用机制

Hearing loss is currently an incurable disease characterized by a paucity of hair cells (HCs) which is followed by the degeneration of spiral ganglion neurons. The most effective therapy for hearing loss is hair cell regeneration. However, the hair cell loss in mammals is irreversible due to the limited capacity to regenerate. Previous studies proved that Wnt activation can promote hair cell regeneration. In previous studies, the applicant found that DAPT is sufficient to promote hair cell regeneration in Gentamicin-damaged basilar membrane by inhibition of Notch signaling pathway. However, the mechanism underlying co-regulation of Wnt and Notch signaling pathway promotes inner ear hair cell regeneration is unclear. Therefore, we hypothesized that Wnt signaling pathway activation and Notch signaling pathway inhibition can promote hair cell regeneration. Meanwhile, the hypothesis was verified based on both cell culture and organ culture experiments step by step. First, We show that co-regulation of Wnt and Notch signaling pathway can promote hair cell fate from ependymal cells and the following mechanism underlying the phenomenon. Second, We show that co-regulation of Wnt and Notch signaling pathway can promote inner ear hair cell generation in the basilar membrane and the following mechanism underlying the phenomenon. Third, We show that co-regulation of Wnt and Notch signaling pathway can promote inner ear hair cell regeneration in the basilar membrane damaged by Gentamicin and the following mechanism underlying the phenomenon. Our study shed a new light for the prevention and therapy for hearing loss.

耳聋是以内耳毛细胞缺失及其引起的神经系统病变为主要表现的疾病，耳聋治疗关键之一是促进内耳毛细胞再生，而哺乳动物内耳毛细胞无法再生。研究表明激活Wnt信号通路促进内耳毛细胞再生。申请者前期研究发现DAPT通过抑制Notch信号通路促进庆大霉素损伤的基底膜毛细胞再生，然而Wnt-Notch信号通路共调控对内耳毛细胞再生的作用及相互作用机制尚未明确。因此，本研究提出如下假设：激活Wnt信号通路同时抑制Notch信号通路可有效促进内耳毛细胞再生。本课题从细胞培养、组织培养方面逐步深入验证该假设：首先证实Wnt-Notch信号通路共调控可促进室管膜细胞转分化为毛细胞样细胞及相关机制；其次建立基底膜体外培养模型，探讨Wnt-Notch信号通路共调控对基底膜毛细胞增殖的影响；再次建立庆大霉素损伤基底膜毛细胞模型，深入探讨Wnt-Notch信号通路共调控促进损伤基底膜毛细胞再生机制，为耳聋防治提供新思路。

本项目研究表明Wnt-Notch信号通路共调控促进内耳毛细胞再生。申请者前期研究发现DAPT通过抑制Notch信号通路促进庆大霉素损伤的基底膜毛细胞再生，然而Wnt-Notch信号通路共调控对内耳毛细胞再生的作用及相互作用机制尚未明确。因此本课题从细胞培养、组织培养方面逐步深入验证：首先证实Wnt-Notch信号通路共调控可促进室管膜细胞转分化为毛细胞样细胞；其次建立基底膜体外培养模型，探讨Wnt-Notch信号通路共调控促进基底膜毛细胞增殖；再次建立庆大霉素损伤基底膜毛细胞模型，深入探讨Wnt-Notch信号通路共调控促进损伤基底膜毛细胞再生，为耳聋防治提供新思路。