《生命科学》 2025, 37(6): 717-723

腺病毒介导Notch与Wnt通路对小鼠内耳毛细胞再生的研究进展

张信文^1,3,* , 翁梦露² , 赵汝霞² , 杨思远^1,2 , 牛巧花² , 曾少举^2,*

¹海南科技职业大学医药学院，海口 571126 ²北京师范大学基因资源与分子发育北京市重点实验室， 北京 100875 ³海南师范大学生命科学学院，海口 571158

摘　要：

人类及其他哺乳动物的耳蜗毛细胞一旦受损便无法再生修复，从而导致永久性的听力损伤。研究发现，通过腺病毒携带特定基因调控 Notch 与Wnt 信号通路，可在小鼠内耳中实现部分毛细胞的再生。通过构建腺病毒NICD-RNAi 抑制 Notch 信号通路，以及β-catenin-AD 激活 Wnt 信号通路，转染庆大霉素损伤的鼠耳蜗后，结果显示较低滴度腺病毒仅转染支持细胞，而较高滴度病毒能同时转染支持细胞和部分毛细胞。NICD-RNAi-AD 能促进支持细胞通过直接转分化再生出毛细胞；β-catenin-AD 能促进支持细胞有丝分裂并向毛细胞分化。这些研究表明，通过腺病毒介导Notch 信号通路的抑制和Wnt 信号通路的激活，实现小鼠毛细胞损伤后的部分再生，这为治疗听力丧失提供了一种新的可能途径。本文对调控Notch 与Wnt 信号通路的机制及其在内耳毛细胞再生中的相关研究进行了系统总结，为未来毛细胞受损后的再生修复予以展望。

通讯作者：张信文 , Email:zhangxw2844@sina.com 曾少举 , Email:sjzeng@bnu.edu.cn

Research progress on adenovirus-mediated Notch and Wnt pathways in the regeneration of hair cells in the mouse inner ear

ZHANG Xin-Wen^1,3,* , WENG Meng-Lu² , ZHAO Ru-Xia² , YANG Si-Yuan^1,2 , NIU Qiao-Hua² , ZENG Shao-Ju^2,*

¹College of Pharmacy, Hainan Vocational University of Science and Technology, Haikou 571126, China ²Beijing Key Laboratory of Gene Resource and Molecular Development, Beijing Normal University, Beijing 100875, China ³College of Life Science, Hainan Normal University, Haikou 571158, China

Abstract:

In humans and other mammals, once the hair cells in the cochlea are damaged, they cannot regenerate naturally, leading to permanent hearing loss. Research has found that by using adenovirus vectors carrying specific genes to regulate the activities of Notch and Wnt signaling pathways, partial regeneration of hair cells can be achieved in the inner ear of mice. Specifically, adenoviral vectors designed to modulate these two signaling pathways were first constructed. By using qt-PCR, it was found that after successful transfection into the inner ear tissue, the activities of Notch signaling pathway have been effectively inhibited by NICD-RNAi while the activities of Wnt signaling pathway have been significantly activated after infection with β-catenin-AD. In the experiment, a mouse model of inner ear hair cell damage was established using gentamicin, observing a gradient increase from the apex to the base of the cochlea. Subsequently, empty adenoviruses were transfected into the inner ear at different titers, revealing that at lower titers, supporting cells were primarily infected by the adenoviruses,  whereas at higher titers, both supporting and hair cells were infected. Further, after NICD-RNAi-AD and β-catenin-AD were separately transfected into the gentamicin-damaged inner ears of mice, the former promoted the direct transdifferentiation of supporting cells into hair cells, while the latter stimulated the mitotic division of supporting cells and guided their differentiation towards hair cells. These results indicate that by using adenovirus vector technology to inhibit the Notch signaling pathway and activate the Wnt signaling pathway, partial regeneration of hair cells can be obtained after inner ear damage in mice, providing new stratagy for the treatment of hearing loss. This review outlines the studies on hair cell regeneration after damage and the mechanisms under which Notch and Wnt signaling pathways are involved in these processes, and also provides some prospects of gene therapy for the loss of hair cells.

Communication Author：ZHANG Xin-Wen , Email:zhangxw2844@sina.com ZENG Shao-Ju , Email:sjzeng@bnu.edu.cn