Mutant astrocytes differentiated from Rett syndrome patients-specific iPSCs have adverse effects on wild-type neurons.
Mutant astrocytes differentiated from Rett syndrome patients-specific iPSCs have adverse effects on wild-type neurons.
复制标题
由雷特综合征患者特异性 iPSC 分化而来的突变星形胶质细胞对野生型神经元有不利影响。
DOI：
10.1093/hmg/ddu008
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发表时间：
2014
影响因子：
3.5
通讯作者：
Chang,Qiang
中科院分区：
文献类型：
--
作者：
Williams,EmilyCunningham;Zhong,Xiaofen;Mohamed,Ahmed;Li,Ronghui;Liu,Yan;Dong,Qiping;Ananiev,GeneE;Mok,JonathanChernChoong;Lin,BenjaminRay;Lu,Jianfeng;Chiao,Cassandra;Cherney,Rachel;Li,Hongda;Zhang,Su-Chun;Chang,Qiang
雷特综合征（RTT）的发病机制尚不清楚。 RTT 小鼠模型的研究表明星形胶质细胞在 RTT 发病机制中具有非细胞自主作用。然而，尚不清楚人类 RTT 星形胶质细胞是否也如此。为了建立体外人类 RTT 模型，我们之前从几名携带不同致病突变的 RTT 患者中生成了同基因诱导多能干细胞 (iPSC) 系。在这里，我们证明这些 RTT iPSC 系可以有效分化为星形胶质细胞祖细胞和保持等基因状态的神经胶质纤维酸性蛋白表达（GFAP+）星形胶质细胞，携带三种不同 RTT 突变的突变 RTT 星形胶质细胞及其条件培养基对野生型神经元的形态和功能有不利影响，并且胶质细胞对神经元形态的影响与突变神经元的内在神经元缺陷无关。此外，我们还发现，胰岛素样生长因子 1 (IGF-1) 和 GPE（一种含有 IGF-1 前 3 个氨基酸的肽）都能够部分挽救由突变 RTT 星形胶质细胞引起的神经元缺陷。我们的研究结果证实了神经胶质对 RTT 病理学的关键贡献，揭示了 IGF-1 治疗的潜在细胞靶点，并进一步验证了患者特异性 iPSC 及其衍生物作为研究 RTT 疾病机制的有价值的工具。
The disease mechanism of Rett syndrome (RTT) is not well understood. Studies in RTT mouse models have suggested a non-cell-autonomous role for astrocytes in RTT pathogenesis. However, it is not clear whether this is also true for human RTT astrocytes. To establish anin vitrohuman RTT model, we previously generated isogenic induced pluripotent stem cell (iPSC) lines from several RTT patients carrying different disease-causing mutations. Here, we show that these RTT iPSC lines can be efficiently differentiated into astroglial progenitors and glial fibrillary acidic protein-expressing (GFAP+) astrocytes that maintain isogenic status, that mutant RTT astrocytes carrying three different RTT mutations and their conditioned media have adverse effects on the morphology and function of wild-type neurons and that the glial effect on neuronal morphology is independent of the intrinsic neuronal deficit in mutant neurons. Moreover, we show that both insulin-like growth factor 1 (IGF-1) and GPE (a peptide containing the first 3 amino acids of IGF-1) are able to partially rescue the neuronal deficits caused by mutant RTT astrocytes. Our findings confirm the critical glial contribution to RTT pathology, reveal potential cellular targets of IGF-1 therapy and further validate patient-specific iPSCs and their derivatives as valuable tools to study RTT disease mechanism.