Combinatorial Atoh1 and Gfi1 induction enhances hair cell regeneration in the adult cochlea.
Combinatorial Atoh1 and Gfi1 induction enhances hair cell regeneration in the adult cochlea.
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DOI：
10.1038/s41598-020-78167-8
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发表时间：
2020-12-08
影响因子：
4.6
通讯作者：
Raphael Y
中科院分区：
文献类型：
--
作者：
Lee S;Song JJ;Beyer LA;Swiderski DL;Prieskorn DM;Acar M;Jen HI;Groves AK;Raphael Y
成熟的哺乳动物耳蜗毛细胞（HC）一旦丢失就不能自发再生，导致终身听力障碍。在成年哺乳动物中诱导HC再生的尝试已经使用HC特异性转录因子Atoh1的过表达，但迄今为止，这种方法产生的HC产生效率低且可变。Gfi1是一种对HC发育和存活非常重要的转录因子。我们评估了Atoh1和Gfi1过表达对HC再生的组合效应，使用基因转移方法在新生儿耳蜗外植体和成年小鼠体内进行。在培养的新生儿耳蜗外植体中，腺病毒过表达Atoh1和Gfi1导致大量异位HC样细胞（HCLC），Atoh1 + Gfi1培养物中的细胞明显多于Atoh1单独培养物。在体外，异位HCLCs出现在内侧到内侧HC的区域以及血管纹中。在成熟的Pou4f3DTR小鼠中进行体内实验，其中HC通过施用白喉毒素而被完全和特异性地消融。耳蜗支持细胞中Atoh1或Atoh1 + Gfi1的腺病毒表达诱导了HCLC的出现，与单独Atoh1相比，Atoh1 + Gfi1表达导致4周后新HCLC增加6.2倍。在整个耳蜗中检测到新的HCLC，表现出不成熟的静纤毛，并存活至少8周。因此，Atoh1和Gfi1的组合诱导是一种有前途的策略，以促进HC再生在成熟的哺乳动物耳蜗。
Mature mammalian cochlear hair cells (HCs) do not spontaneously regenerate once lost, leading to life-long hearing deficits. Attempts to induce HC regeneration in adult mammals have used over-expression of the HC-specific transcription factor Atoh1, but to date this approach has yielded low and variable efficiency of HC production. Gfi1 is a transcription factor important for HC development and survival. We evaluated the combinatorial effects of Atoh1 and Gfi1 over-expression on HC regeneration using gene transfer methods in neonatal cochlear explants, and in vivo in adult mice. Adenoviral over-expression of Atoh1 and Gfi1 in cultured neonatal cochlear explants resulted in numerous ectopic HC-like cells (HCLCs), with significantly more cells in Atoh1 + Gfi1 cultures than Atoh1 alone. In vitro, ectopic HCLCs emerged in regions medial to inner HCs as well as in the stria vascularis. In vivo experiments were performed in mature Pou4f3DTR mice in which HCs were completely and specifically ablated by administration of diphtheria toxin. Adenoviral expression of Atoh1 or Atoh1 + Gfi1 in cochlear supporting cells induced appearance of HCLCs, with Atoh1 + Gfi1 expression leading to 6.2-fold increase of new HCLCs after 4 weeks compared to Atoh1 alone. New HCLCs were detected throughout the cochlea, exhibited immature stereocilia and survived for at least 8 weeks. Combinatorial Atoh1 and Gfi1 induction is thus a promising strategy to promote HC regeneration in the mature mammalian cochlea.
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影响因子：
7.3
作者：
Doetzlhofer A;Avraham KB
通讯作者：
Avraham KB
影响因子：
64.8
作者：
Gubbels, Samuel P.;Woessner, David W.;Mitchell, John C.;Ricci, Anthony J.;Brigande, John V.
通讯作者：
Brigande, John V.
影响因子：
3.5
作者：
Hertzano, R;Montcouquiol, M;Avraham, KB
通讯作者：
Avraham, KB
DOI：
10.1073/pnas.1402898111
发表时间：
2014-04-08
影响因子：
11.1
作者：
Jiang, Linjia;Romero-Carvajal, Andres;Piotrowski, Tatjana
通讯作者：
Piotrowski, Tatjana
影响因子：
12.4
作者：
Du, Xiaoping;Cai, Qunfeng;Kopke, Richard D.
通讯作者：
Kopke, Richard D.