Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells.
Dual expression of Atoh1 and Ikzf2 promotes transformation of adult cochlear supporting cells into outer hair cells.
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作者：
Sun S;Li S;Luo Z;Ren M;He S;Wang G;Liu Z
哺乳动物耳蜗外毛细胞 (OHC) 对于听力至关重要。 OHC 变性后会出现严重的听力障碍。之前从耳蜗支持细胞 (SC) 再生新 OHC 的尝试并未成功，特别是缺乏关键 OHC 运动蛋白 Prestin 的表达。因此，Prestin+ OHC 的再生代表了恢复体内听觉功能的障碍。在这里，我们报道了通过同时诱导 OHC 发育所必需的两个关键转录因子：Atoh1 和 Ikzf2，成年小鼠耳蜗 SC 在体内成功转化为 Prestin+ OHC 样细胞。单细胞RNA测序揭示了OHC样细胞中729个OHC基因的上调和331个SC基因的下调。这些 OHC 样细胞的分化状态比以前达到的要先进得多。因此，这项研究建立了一种诱导 Prestin+ OHC 再生的有效方法，为通过 SC 转分化进行体内耳蜗修复铺平了道路。
Mammalian cochlear outer hair cells (OHCs) are essential for hearing. Severe hearing impairment follows OHC degeneration. Previous attempts at regenerating new OHCs from cochlear supporting cells (SCs) have been unsuccessful, notably lacking expression of the key OHC motor protein, Prestin. Thus, regeneration of Prestin+ OHCs represents a barrier to restore auditory function in vivo. Here, we reported the successful in vivo conversion of adult mouse cochlear SCs into Prestin+ OHC-like cells through the concurrent induction of two key transcriptional factors known to be necessary for OHC development: Atoh1 and Ikzf2. Single-cell RNA sequencing revealed the upregulation of 729 OHC genes and downregulation of 331 SC genes in OHC-like cells. The resulting differentiation status of these OHC-like cells was much more advanced than previously achieved. This study thus established an efficient approach to induce the regeneration of Prestin+ OHCs, paving the way for in vivo cochlear repair via SC transdifferentiation.