AAV8-mediated Atoh1 overexpression induces dose-dependent regeneration of vestibular hair cells in adult mice
AAV8-mediated Atoh1 overexpression induces dose-dependent regeneration of vestibular hair cells in adult mice
复制标题
AAV8介导的Atoh1过表达诱导成年小鼠前庭毛细胞的剂量依赖性再生
DOI：
10.1016/j.neulet.2021.135679
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发表时间：
2021-02-08
影响因子：
2.5
通讯作者：
Wang, Guo-Peng
中科院分区：
文献类型：
--
作者：
Guo, Jing-Ying;He, Lu;Wang, Guo-Peng
前庭毛细胞（HCs）是用于检测头部运动的机械感受器。成年哺乳动物的前庭毛细胞在受损后无法完全再生，从而导致前庭功能障碍。Atoh1的过表达可有效诱导毛细胞再生。然而，具有临床可行性的方法以及再生程度的提高均是需要的。在此我们使用了两种不同滴度的腺相关病毒（AAV）8型载体在成年小鼠受损的椭圆囊中过表达Atoh1。病毒接种一个月后，观察到大量的肌球蛋白VIIa阳性细胞和未成熟的静纤毛。定量分析显示，Atoh1过表达以剂量依赖的方式补充前庭毛细胞。较高滴度的载体相较于较低滴度的载体增加了肌球蛋白VIIa阳性细胞的数量。此外，只有较高滴度组中的Atoh1过表达增强了静纤毛再生，这是再生毛细胞成熟的重要步骤。尽管目前的治疗未能使动物的功能恢复，但我们的结果促使进一步改进通过AAV对前庭功能障碍的恢复。
Vestibular hair cells (HCs) are mechanoreceptors for the detection of head movement. Vestibular HCs of adult mammals never completely regenerate after damage, resulting in vestibular dysfunction. Overexpression of Atoh1 is effective for inducing HC regeneration. However, method of clinical feasibility and improvement of regenerative extent are both in need. Here we used an adeno-associated virus (AAV) serotype 8 vector of two different titers to overexpress Atoh1 in the injured utricles of adult mice. One month after virus inoculation, abundant myosin VIIa-positive cells and immature stereocilia were observed. Quantitative analyses revealed that Atoh1 overexpression replenished vestibular HCs in a dose-dependent manner. Vectors of a higher titer increased the number of myosin VIIa-positive cells compared to those of lower titer. Moreover, only Atoh1 overexpression in the higher titer group enhanced stereocilium regeneration, which is an important step in the maturation of regenerated HCs. Although the current treatment failed to initiate functional recovery of the animals, our results prompt further improvements in the recovery of vestibular dysfunction by AAV.