Modeling Gap junction beta 2 gene-related deafness with human iPS
Modeling Gap junction beta 2 gene-related deafness with human iPS
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使用人类 iPS 模拟间隙连接 beta 2 基因相关性耳聋
DOI：
10.1093/hmg/ddab097
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发表时间：
2021
影响因子：
3.5
通讯作者：
Kazusaku Kamiya
中科院分区：
文献类型：
--
作者：
Ichiro Fukunaga;Yoko Oe;Keiko Danzaki;Sayaka Ohta;Cheng Chen;Kyoko Shirai;Atsushi Kawano;Katsuhisa Ikeda;Kazusaku Kamiya
有超过120种形式的非综合征性耳聋与已确定的遗传基因座有关。特别是，编码连接蛋白（CX）26蛋白的差距连接β 2基因（GJB 2）突变是全世界遗传性耳聋的最常见原因。我们先前描述了一种诱导方法，从小鼠诱导的多能干细胞（iPSC）中培养功能性CX 26间隙连接形成细胞，并在GJB 2相关耳聋的体外模型中产生。然而，尚未报道来源于人iPSC或胚胎干细胞（ESC）的功能性CX 26间隙连接形成细胞。在这项研究中，我们产生了人iPSC衍生的功能性CX 26间隙连接形成细胞（iCX 26 GJC），其具有耳蜗支持细胞的特征。这些iCX 26 GJC在细胞-细胞边界处具有间隙连接斑块样形成，并且共表达在耳蜗支持细胞中表达的几种标志物。此外，我们从两名亚洲最常见的GJB 2突变患者的iPSC中产生了iCX 26 GJC，这些细胞再现了GJB 2相关耳聋的病理学。这些体外模型可能对GJB 2相关耳聋的各种突变的最佳治疗和药物筛选有用。
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 generatedin vitromodels forGJB2-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 commonGJB2mutation in Asia, and these cells reproduced the pathology ofGJB2-related deafness. Thesein vitromodels may be useful for establishing optimal therapies and drug screening for various mutations inGJB2-related deafness.