Generation of mature and functional hair cells by co-expression of Gfi1, Pou4f3, and Atoh1 in the postnatal mouse cochlea
Generation of mature and functional hair cells by co-expression of Gfi1, Pou4f3, and Atoh1 in the postnatal mouse cochlea
复制标题
通过在出生后小鼠耳蜗中共表达 Gfi1、Pou4f3 和 Atoh1 生成成熟且有功能的毛细胞
DOI：
10.1016/j.celrep.2021.109016
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发表时间：
2021-04-20
期刊：
影响因子：
8.8
通讯作者：
Li, Huawei
中科院分区：
文献类型：
--
作者：
Chen, Yan;Gu, Yuyan;Li, Huawei
哺乳动物耳蜗不能自发再生功能性毛细胞。Atoh1过表达以及其他策略不能产生功能性HC。在这里，我们同时上调Gfi1，Pou4f3和Atoh1的表达在出生后耳蜗支持细胞（SC）在体内，有效地将SC转化为HC。新再生的HC表达HC标记物Myo7a、钙结合蛋白、小清蛋白和Ctbp2，并受神经突支配。重要的是，许多新的HC表达成熟和终末标志物普雷斯廷或囊泡谷氨酸转运蛋白3（vGlut 3），这取决于源SC的亚型。最后，我们的膜片钳分析表明，在内侧区域的新的HC获得了一个大的K+电流，发射尖峰瞬时，并表现出签名细化带状突触功能，在接近本地野生型内部HC。我们证明，共同上调Gfi1，Pou4f3和Atoh1增强HC生成的效率，并促进新HC的功能成熟。
The mammalian cochlea cannot regenerate functional hair cells (HCs) spontaneously. Atoh1 overexpression as well as other strategies are unable to generate functional HCs. Here, we simultaneously upregulated the expression of Gfi1, Pou4f3, and Atoh1 in postnatal cochlear supporting cells (SCs) in vivo, which efficiently converted SCs into HCs. The newly regenerated HCs expressed HC markers Myo7a, Calbindin, Parvalbumin, and Ctbp2 and were innervated by neurites. Importantly, many new HCs expressed the mature and terminal marker Prestin or vesicular glutamate transporter 3 (vGlut3), depending on the subtypes of the source SCs. Finally, our patch-clamp analysis showed that the new HCs in the medial region acquired a large K+ current, fired spikes transiently, and exhibited signature refinement of ribbon synapse functions, in close resemblance to native wild-type inner HCs. We demonstrated that co-upregulating Gfi1, Pou4f3, and Atoh1 enhances the efficiency of HC generation and promotes the functional maturation of new HCs.