The mechanoreceptive sensory hair cells in the inner ear are selectively vulnerable to numerous genetic and environmental insults. In mammals, hair cells lack regenerative capacity, and their death leads to permanent hearing loss and vestibular dysfunction. Their paucity and inaccessibility has limited the search for otoprotective and regenerative strategies. Growing hair cells in vitro would provide a route to overcome this experimental bottleneck. We report a combination of four transcription factors (Six1, Atoh1, Pou4f3, and Gfi1) that can convert mouse embryonic fibroblasts, adult tail-tip fibroblasts and postnatal supporting cells into induced hair cell-like cells (iHCs). iHCs exhibit hair cell-like morphology, transcriptomic and epigenetic profiles, electrophysiological properties, mechanosensory channel expression, and vulnerability to ototoxin in a high-content phenotypic screening system. Thus, direct reprogramming provides a platform to identify causes and treatments for hair cell loss, and may help identify future gene therapy approaches for restoring hearing.

中文翻译：

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原代体细胞直接谱系转化产生内耳毛细胞

内耳中的机械感受性感觉毛细胞选择性地易受多种遗传和环境侵害。在哺乳动物中，毛细胞缺乏再生能力，它们的死亡会导致永久性听力损失和前庭功能障碍。它们的匮乏和交通不便限制了对耳保护和再生策略的研究。在体外培养毛细胞将为克服这一实验瓶颈提供一条途径。我们报告了四种转录因子（Six1、Atoh1、Pou4f3 和 Gfi1）的组合，它们可以将小鼠胚胎成纤维细胞、成人尾尖成纤维细胞和出生后支持细胞转化为诱导毛细胞样细胞 (iHC)。iHC 表现出毛细胞样形态、转录组学和表观遗传学特征、电生理学特性、机械感觉通道表达、以及高内涵表型筛选系统中对耳毒素的脆弱性。因此，直接重编程提供了一个平台来确定毛细胞丢失的原因和治疗方法，并可能有助于确定未来恢复听力的基因治疗方法。