Department of Neurobiology, University of Chicago, Chicago, Illinois 60637.
The Virginia Merrill Bloedel Hearing Research Center and the Department of Otolaryngology Head and Neck Surgery, University of Washington, Seattle, Washington 98195.
J Neurosci. 2021 Sep 15;41(37):7779-7796. doi: 10.1523/JNEUROSCI.3127-20.2021. Epub 2021 Jul 23.
Aging, disease, and trauma can lead to loss of vestibular hair cells and permanent vestibular dysfunction. Previous work showed that, following acute destruction of ∼95% of vestibular hair cells in adult mice, ∼20% regenerate naturally (without exogenous factors) through supporting cell transdifferentiation. There is, however, no evidence for the recovery of vestibular function. To gain insight into the lack of functional recovery, we assessed functional differentiation in regenerated hair cells for up to 15 months, focusing on key stages in stimulus transduction and transmission: hair bundles, voltage-gated conductances, and synaptic contacts. Regenerated hair cells had many features of mature type II vestibular hair cells, including polarized mechanosensitive hair bundles with zone-appropriate stereocilia heights, large voltage-gated potassium currents, basolateral processes, and afferent and efferent synapses. Regeneration failed, however, to recapture the full range of properties of normal populations, and many regenerated hair cells had some properties of immature hair cells, including small transduction currents, voltage-gated sodium currents, and small or absent HCN (hyperpolarization-activated cyclic nucleotide-gated) currents. Furthermore, although mouse vestibular epithelia normally have slightly more type I hair cells than type II hair cells, regenerated hair cells acquired neither the low-voltage-activated potassium channels nor the afferent synaptic calyces that distinguish mature type I hair cells from type II hair cells and confer distinctive physiology. Thus, natural regeneration of vestibular hair cells in adult mice is limited in total cell number, cell type diversity, and extent of cellular differentiation, suggesting that manipulations are needed to promote full regeneration with the potential for recovery of vestibular function. Death of inner ear hair cells in adult mammals causes permanent loss of hearing and balance. In adult mice, the sudden death of most vestibular hair cells stimulates the production of new hair cells but does not restore balance. We investigated whether the lack of systems-level function reflects functional deficiencies in the regenerated hair cells. The regenerated population acquired mechanosensitivity, voltage-gated channels, and afferent synapses, but did not reproduce the full range of hair cell types. Notably, no regenerated cells acquired the distinctive properties of type I hair cells, a major functional class in amniote vestibular organs. To recover vestibular system function in adults, we may need to solve how to regenerate the normal variety of mature hair cells.
衰老、疾病和创伤会导致前庭毛细胞丧失和永久性前庭功能障碍。以前的工作表明，在成年小鼠的前庭毛细胞急性破坏约 95%后，约 20%的前庭毛细胞会在没有外源因素的情况下通过支持细胞转分化自然再生。然而，目前还没有证据表明前庭功能得到了恢复。为了深入了解功能恢复缺失的原因，我们在长达 15 个月的时间内评估了再生毛细胞的功能分化，重点关注刺激转导和传递的关键阶段：毛细胞束、电压门控电导和突触接触。再生的毛细胞具有许多成熟的 II 型前庭毛细胞的特征，包括具有适当立体纤毛高度的极化机械敏感毛细胞束、大的电压门控钾电流、基底外侧过程以及传入和传出突触。然而，再生未能重现正常群体的全部特性，许多再生的毛细胞具有一些不成熟毛细胞的特性，包括小的转导电流、电压门控钠电流以及小的或不存在 HCN（超极化激活环核苷酸门控）电流。此外，尽管小鼠前庭上皮通常具有比 II 型毛细胞略多的 I 型毛细胞，但再生的毛细胞既没有获得低电压激活的钾通道，也没有获得将成熟 I 型毛细胞与 II 型毛细胞区分开来并赋予独特生理学特性的传入突触小球。因此，成年小鼠前庭毛细胞的自然再生在细胞总数、细胞类型多样性和细胞分化程度方面受到限制，这表明需要进行操作以促进完全再生，并有可能恢复前庭功能。成年哺乳动物内耳毛细胞的死亡会导致听力和平衡的永久性丧失。在成年小鼠中，大多数前庭毛细胞的突然死亡会刺激新毛细胞的产生，但不会恢复平衡。我们研究了缺乏系统水平功能是否反映了再生毛细胞的功能缺陷。再生群体获得了机械敏感性、电压门控通道和传入突触，但没有再现毛细胞类型的全部范围。值得注意的是，没有再生细胞获得 I 型毛细胞的独特特性，I 型毛细胞是羊膜动物前庭器官的主要功能类别。为了在成年人中恢复前庭系统功能，我们可能需要解决如何再生正常的成熟毛细胞多样性的问题。
