In vivo generation of immature inner hair cells in neonatal mouse cochleae by ectopic Atoh1 expression.
In vivo generation of immature inner hair cells in neonatal mouse cochleae by ectopic Atoh1 expression.
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DOI：
10.1371/journal.pone.0089377
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Zuo J
中科院分区：
文献类型：
--
作者：
Liu Z;Fang J;Dearman J;Zhang L;Zuo J
听觉毛细胞再生是一种很有前途的听力恢复方法。最近的研究表明，诱导的多能干细胞/胚胎干细胞或邻近HCS的支持细胞(SCs)可以转化为HC命运。然而，关于新的HC是外层还是内层HC的特征，我们知之甚少。在这里，我们展示了两种SCs亚型，内缘细胞(IBS)和内指节细胞(IPHS)，向内侧HC(IHC)命运的转化。这是通过异位激活IBS/IPHS中的Atoh1实现的，Atoh1是HC命运所必需的转录因子。Atoh1+IBS/IPHS首先打开另一个HC转录因子Pou4f3，然后表达8个HC标记。转化率从1周龄的∼2.4%逐渐增加到成年的∼17.8%。有趣的是，新的HC表现出IHC的特征，如直线形的立体纤毛束，Fgf8和Otoferlin的表达，以及存在比外部HC更大的外向电流。然而，新的HC缺乏IHC终末分化标志物vGlut3，突触前Cbtp2点状突触密度降低，突触后GluR2特化很少，并显示未成熟的IHC外向电流。我们的结果表明，体内异位表达Atoh1的IBS/IPHS转化为IHC命运的速度更快更快，转化更彻底，但这些新的IHC在末端分化之前就被阻止了。因此，IBS/IPHS是体内再生IHC的良好候选材料。
Regeneration of auditory hair cells (HCs) is a promising approach to restore hearing. Recent studies have demonstrated that induced pluripotent stem cells/embryonic stem cells or supporting cells (SCs) adjacent to HCs can be converted to adopt the HC fate. However, little is known about whether new HCs are characteristic of outer or inner HCs. Here, we showed in vivo conversion of 2 subtypes of SCs, inner border cells (IBs) and inner phalangeal cells (IPhs), to the inner HC (IHC) fate. This was achieved by ectopically activating Atoh1, a transcription factor necessary for HC fate, in IBs/IPhs at birth. Atoh1+ IBs/IPhs first turned on Pou4f3, another HC transcription factor, before expressing 8 HC markers. The conversion rate gradually increased from ∼2.4% at 1 week of age to ∼17.8% in adult. Interestingly, new HCs exhibited IHC characteristics such as straight line–shaped stereociliary bundles, expression of Fgf8 and otoferlin, and presence of larger outward currents than those of outer HCs. However, new HCs lacked the terminal differentiation IHC marker vGlut3, exhibited reduced density of presynaptic Cbtp2 puncta that had little postsynaptic GluR2 specialization, and displayed immature IHC outward currents. Our results demonstrate that the conversion rate of IBs/IPhs in vivo by Atoh1 ectopic expression into the IHC fate was higher and faster and the conversion was more complete than that of the 2 other SC subtypes underneath the outer HCs; however, these new IHCs are arrested before terminal differentiation. Thus, IBs/IPhs are good candidates to regenerate IHCs in vivo.
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