Cochlear Cell Modeling Using Disease-Specific iPSCs Unveils a Degenerative Phenotype and Suggests Treatments for Congenital Progressive Hearing Loss
Cochlear Cell Modeling Using Disease-Specific iPSCs Unveils a Degenerative Phenotype and Suggests Treatments for Congenital Progressive Hearing Loss
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DOI：
10.1016/j.celrep.2016.12.020
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发表时间：
2017-01-03
期刊：
影响因子：
8.8
通讯作者：
Okano, Hideyuki
中科院分区：
文献类型：
--
作者：
Hosoya, Makoto;Fujioka, Masato;Okano, Hideyuki
听力障碍是先天性缺陷最常见的症状，并且通常难以治疗。Pendred综合征是遗传性听力损失最常见的综合征形式，与阴离子交换蛋白pendrin的突变有关。pendrin作为阴离子交换剂的功能丧失被认为是病因，但啮齿动物模型不表现出进行性耳聋。在这里，我们报告了一种退行性表型，表现出突变的pendrin聚集体和增加的易感性，从患者来源的诱导多能干细胞（iPSC）诱导的耳蜗上皮细胞的细胞应激。这些退化的表型被拯救的位点特异性基因校正。此外，低剂量的雷帕霉素和二甲双胍减少了聚集和细胞死亡。我们的研究结果提供了一个意想不到的，全面的理解耳聋由于“退行性耳蜗疾病”，并可能有助于合理的治疗发展。这种基于iPSC的疾病模型为研究遗传性听力损失的发病机制和治疗开发提供了一种方法。
Hearing impairments are the most common symptom of congenital defects, and they generally remain intractable to treatment. Pendred syndrome, the most frequent syndromic form of hereditary hearing loss, is associated with mutations in the anion exchanger pendrin. Loss of pendrin function as an anion exchanger is thought to be causative, but rodent models do not exhibit progressive deafness. Here, we report a degenerative phenotype exhibiting mutant pendrin aggregates and increased susceptibility to cellular stresses in cochlear epithelial cells induced from patient-derived induced pluripotent stem cells (iPSCs). These degenerative phenotypes were rescued by site-specific gene corrections. Moreover, low-dose rapamycin and metformin reduced aggregation and cell death. Our results provide an unexpected, comprehensive understanding of deafness due to "degenerative cochlear disease'' and may contribute to rational therapeutic development. This iPSC-based disease model provides an approach to the study of pathogenesis and therapeutic development for hereditary hearing loss.