Generation of hair cells in neonatal mice by β-catenin overexpression in Lgr5-positive cochlear progenitors
Generation of hair cells in neonatal mice by β-catenin overexpression in Lgr5-positive cochlear progenitors
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DOI：
10.1073/pnas.1219952110
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发表时间：
2013-08-20
影响因子：
11.1
通讯作者：
Edge, Albert S. B.
中科院分区：
文献类型：
--
作者：
Shi, Fuxin;Hua, Lingxiang;Edge, Albert S. B.
哺乳动物的毛细胞不能再生，它们的丧失是导致耳聋的主要原因。我们最近在体外发现了富含亮氨酸重复序列、表达G蛋白偶联受体5(Lgr5)的耳蜗支撑细胞，具有自我更新和毛细胞分化的能力。我们发现，这些细胞是耳蜗支持细胞的一个子集，对Wnt信号有反应。在这里，我们询问这些Lgr5阳性细胞，尽管它们在变性丢失后缺乏对毛细胞替代的贡献，但是否可以通过强制表达β-连环蛋白来驱动体内毛细胞前体的作用。我们发现，在新生动物中，支持细胞中β-连环蛋白的强制稳定导致了支持细胞的增殖和毛细胞的产生。虽然β-连环蛋白在所有支持细胞中的表达都通过遗传手段增加，但正常有丝分裂后细胞进入细胞周期和向毛细胞分化仅限于Lgr5阳性群体。我们的发现表明，Wnt/β-catenin可以驱动Lgr5阳性细胞作为毛细胞前体细胞，即使它们退出了细胞周期并明显确定了细胞命运。
Mammalian hair cells do not regenerate, and their loss is a major cause of deafness. We recently identified leucine-rich repeat containing, G-protein-coupled receptor 5 (Lgr5)-expressing cochlear supporting cells with the capacity for self-renewal and hair cell differentiation in vitro. We found that these cells, a subset of cochlear supporting cells, were responsive to Wnt signaling. Here we asked whether these Lgr5-positive cells, despite their lack of contribution to hair cell replacement after degenerative loss, could be driven by forced expression of beta-catenin to act as hair cell progenitors in vivo. We showed that forced stabilization of beta-catenin in supporting cells in neonatal animals resulted in proliferation of supporting cells and generation of hair cells. Although beta-catenin expression was increased by genetic means in all supporting cells, entry to the cell cycle and differentiation to hair cells of the normally postmitotic cells was restricted to the Lgr5-positive population. Our finding suggests that Wnt/beta-catenin can drive Lgr5-positive cells to act as hair cell progenitors, even after their exit from the cell cycle and apparent establishment of cell fate.