Abstract：
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.
摘要：
耳蜗内毛细胞（IHC）是主要的声音受体，因此是开发听力障碍治疗的目标。体内IHC再生已被广泛尝试，虽然尚未在IHC损伤的耳蜗中。此外，新的IHC与野生型IHC相似的程度尚不清楚，新的IHC改善听力的能力也是如此。这里,我们开发了一种体内小鼠模型,其中野生型IHC被预损伤,非感觉支持细胞通过瞬时异位表达Atoh1和永久表达Tbx2转化为IHC.值得注意的是,新的IHC表达功能标记vGlut3，并呈现与野生型IHC相似的转录组和电生理特性。此外，新IHC的形成效率和成熟度高于先前报道的，虽然听力没有显著改善，至少部分是由于新IHC中的机电转换（MET）缺陷。因此，在受损的耳蜗中，我们已经成功地再生了在许多方面类似于野生型IHC的新IHC。我们的发现表明，有缺陷的MET是阻止听力恢复的关键障碍，因此应促进未来的IHC再生研究。
