Wnt activation followed by Notch inhibition promotes mitotic hair cell regeneration in the postnatal mouse cochlea.
Wnt activation followed by Notch inhibition promotes mitotic hair cell regeneration in the postnatal mouse cochlea.
复制标题
Wnt 激活和 Notch 抑制促进出生后小鼠耳蜗有丝分裂毛细胞再生
DOI：
10.18632/oncotarget.11479
复制
发表时间：
2016-10-11
期刊：
影响因子：
--
通讯作者：
Li H
中科院分区：
文献类型：
--
作者：
Ni W;Zeng S;Li W;Chen Y;Zhang S;Tang M;Sun S;Chai R;Li H
毛细胞（HC）的损失是哺乳动物永久性听力损失的主要原因。先前的研究已经报道，在新生小鼠耳蜗中，Wnt激活促进支持细胞（SC）增殖，Notch抑制促进SC向HC的转分化。然而，单独的Wnt激活不能再生大量的新HC，单独的Notch抑制以耗尽SC群体为代价再生HC，这导致新再生的HC死亡。有丝分裂HC再生可能在再生HC的同时保留SC数量，这可能是一种更好的HC长期再生方法。我们提出了一个两步的基因操作，Wnt激活，然后Notch抑制，完成有丝分裂再生的HC，同时部分保留SC的数量。我们发现，Wnt激活后，Notch抑制强烈促进有丝分裂再生的新的HC在正常和新霉素损伤的耳蜗，同时部分保留SC数量。谱系追踪显示，大多数有丝分裂再生的HC特异性地衍生自具有或不具有HC损伤的Lgr5+祖细胞。我们的研究结果表明，Wnt和Notch信号的共同调节可能提供一个更好的方法，有丝分裂再生HC从Lgr5+祖细胞。
Hair cell (HC) loss is the main cause of permanent hearing loss in mammals. Previous studies have reported that in neonatal mice cochleae, Wnt activation promotes supporting cell (SC) proliferation and Notch inhibition promotes the trans-differentiation of SCs into HCs. However, Wnt activation alone fails to regenerate significant amounts of new HCs, Notch inhibition alone regenerates the HCs at the cost of exhausting the SC population, which leads to the death of the newly regenerated HCs. Mitotic HC regeneration might preserve the SC number while regenerating the HCs, which could be a better approach for long-term HC regeneration. We present a two-step gene manipulation, Wnt activation followed by Notch inhibition, to accomplish mitotic regeneration of HCs while partially preserving the SC number. We show that Wnt activation followed by Notch inhibition strongly promotes the mitotic regeneration of new HCs in both normal and neomycin-damaged cochleae while partially preserving the SC number. Lineage tracing shows that the majority of the mitotically regenerated HCs are derived specifically from the Lgr5+ progenitors with or without HC damage. Our findings suggest that the co-regulation of Wnt and Notch signaling might provide a better approach to mitotically regenerate HCs from Lgr5+ progenitor cells.