Department of Otorhinolaryngology, Juntendo University Faculty of Medicine, Tokyo 1138421, Japan.
Department of Otolaryngology, Head and Neck Surgery, Tokyo Medical University, Tokyo 1600023, Japan.
Hum Mol Genet. 2021 Jul 9;30(15):1429-1442. doi: 10.1093/hmg/ddab097.
There are >120 forms of non-syndromic deafness associated with identified genetic loci. In particular, mutation of the gap junction beta 2 gene (GJB2), which encodes connexin (CX)26 protein, is the most frequent cause of hereditary deafness worldwide. We previously described an induction method to develop functional CX26 gap junction-forming cells from mouse-induced pluripotent stem cells (iPSCs) and generated in vitro models for GJB2-related deafness. However, functional CX26 gap junction-forming cells derived from human iPSCs or embryonic stem cells (ESCs) have not yet been reported. In this study, we generated human iPSC-derived functional CX26 gap junction-forming cells (iCX26GJCs), which have the characteristics of cochlear supporting cells. These iCX26GJCs had gap junction plaque-like formations at cell-cell borders and co-expressed several markers that are expressed in cochlear supporting cells. Furthermore, we generated iCX26GJCs derived from iPSCs from two patients with the most common GJB2 mutation in Asia, and these cells reproduced the pathology of GJB2-related deafness. These in vitro models may be useful for establishing optimal therapies and drug screening for various mutations in GJB2-related deafness.
有超过 120 种与已确定遗传基因座相关的非综合征性耳聋。特别是，连接蛋白（CX）26 基因突变是导致全球遗传性耳聋的最常见原因，该基因突变发生在缝隙连接β 2 基因（GJB2）上，该基因编码连接蛋白（CX）26 蛋白。我们之前描述了一种诱导方法，可从诱导多能干细胞（iPSCs）中开发功能性 CX26 缝隙连接形成细胞，并生成 GJB2 相关耳聋的体外模型。然而，尚未报道从人 iPSC 或胚胎干细胞（ESCs）中获得功能性 CX26 缝隙连接形成细胞。在这项研究中，我们生成了具有耳蜗支持细胞特征的人 iPSC 衍生的功能性 CX26 缝隙连接形成细胞（iCX26GJCs）。这些 iCX26GJCs 在细胞-细胞边界处具有缝隙连接斑状形成，并共表达了在耳蜗支持细胞中表达的几种标志物。此外，我们从亚洲最常见的 GJB2 突变的两个患者的 iPSCs 中生成了 iCX26GJCs，这些细胞再现了 GJB2 相关耳聋的病理学。这些体外模型可能有助于为 GJB2 相关耳聋的各种突变建立最佳治疗和药物筛选方法。
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