In situ regeneration of inner hair cells in the damaged cochlea by temporally regulated co-expression of Atoh1 and Tbx2.
In situ regeneration of inner hair cells in the damaged cochlea by temporally regulated co-expression of Atoh1 and Tbx2.
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DOI：
10.1242/dev.201888
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发表时间：
2023-12
期刊：
影响因子：
4.6
通讯作者：
Xiang Li;Minhui Ren;Yunpeng Gu;Tong Zhu;Yu Zhang;Jie Li;Chao Li;Guangqin Wang;Lei Song-Lei
中科院分区：
文献类型：
--
作者：
Xiang Li;Minhui Ren;Yunpeng Gu;Tong Zhu;Yu Zhang;Jie Li;Chao Li;Guangqin Wang;Lei Song-Lei
耳蜗内毛细胞（IHC）是主要的声音感受器，因此是开发听力障碍治疗的目标。尽管尚未在IHC损伤的耳蜗中进行，但已广泛尝试了体内IHC再生。此外，新的IHC与野生型IHC相似的程度仍不清楚，新的IHC改善听力的能力也不清楚。在这里，我们已经开发了一种体内小鼠模型，其中野生型IHC的预损伤和非感觉支持细胞转化为IHC异位表达Atoh1瞬时和Tbx2永久。值得注意的是，新的IHC表达功能标志物vGlut3，并呈现出与野生型IHC相似的转录组学和电生理学特性。此外，新的IHC的形成效率和成熟度高于以前报道的，虽然没有实现显着的听力改善，至少部分是由于有缺陷的机电转导（MET）在新的IHC。因此，我们已经成功地再生新的IHC类似野生型IHC在许多方面在受损的耳蜗。我们的研究结果表明，有缺陷的MET是一个关键的障碍，阻止听力恢复的能力，因此应促进未来的IHC再生研究。
Cochlear inner hair cells (IHCs) are primary sound receptors, and are therefore a target for developing treatments for hearing impairment. IHC regeneration in vivo has been widely attempted, although not yet in the IHC-damaged cochlea. Moreover, the extent to which new IHCs resemble wild-type IHCs remains unclear, as is the ability of new IHCs to improve hearing. Here, we have developed an in vivo mouse model wherein wild-type IHCs were pre-damaged and nonsensory supporting cells were transformed into IHCs by ectopically expressing Atoh1 transiently and Tbx2 permanently. Notably, the new IHCs expressed the functional marker vGlut3 and presented similar transcriptomic and electrophysiological properties to wild-type IHCs. Furthermore, the formation efficiency and maturity of new IHCs were higher than those previously reported, although marked hearing improvement was not achieved, at least partly due to defective mechanoelectrical transduction (MET) in new IHCs. Thus, we have successfully regenerated new IHCs resembling wild-type IHCs in many respects in the damaged cochlea. Our findings suggest that the defective MET is a critical barrier that prevents the restoration of hearing capacity and should thus facilitate future IHC regeneration studies.