Modeling retinal degeneration using patient-specific induced pluripotent stem cells.
Modeling retinal degeneration using patient-specific induced pluripotent stem cells.
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DOI：
10.1371/journal.pone.0017084
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发表时间：
2011-02-10
期刊：
影响因子：
3.7
通讯作者：
Takahashi M
中科院分区：
文献类型：
--
作者：
Jin ZB;Okamoto S;Osakada F;Homma K;Assawachananont J;Hirami Y;Iwata T;Takahashi M
视网膜色素变性是人类最常见的遗传性眼病，可导致夜盲和视力缺陷。众所周知，这种疾病是由杆状感光细胞退化引起的；然而，由于无法获得用于机制研究和药物筛选的疾病特异性人类光感受器细胞，它仍然是不可治愈的。我们从5例RP1、RP9、PRPH2或RHO基因突变的RP患者中获得成纤维细胞，并通过异位表达四个关键的重编程因子来产生患者特异性的诱导多能干细胞(IPS)。我们将iPS细胞分化为患者丢失的杆状感光细胞，发现它们具有合适的免疫细胞化学特征和电生理特性。有趣的是，具有不同突变的患者来源的杆状细胞的数量在体外减少；来自特定突变的患者来源的细胞表达氧化或内质网应激的标志，并且对维生素E的反应与临床试验中观察到的不同。总体而言，患者来源的杆状细胞重现了疾病的表型，并表达了细胞应激的标志。我们的结果表明，使用患者来源的iPS细胞将有助于阐明RP基因突变引起的致病机制。
Retinitis pigmentosa (RP) is the most common inherited human eye disease resulting in night blindness and visual defects. It is well known that the disease is caused by rod photoreceptor degeneration; however, it remains incurable, due to the unavailability of disease-specific human photoreceptor cells for use in mechanistic studies and drug screening. We obtained fibroblast cells from five RP patients with distinct mutations in the RP1, RP9, PRPH2 or RHO gene, and generated patient-specific induced pluripotent stem (iPS) cells by ectopic expression of four key reprogramming factors. We differentiated the iPS cells into rod photoreceptor cells, which had been lost in the patients, and found that they exhibited suitable immunocytochemical features and electrophysiological properties. Interestingly, the number of the patient-derived rod cells with distinct mutations decreased in vitro; cells derived from patients with a specific mutation expressed markers for oxidation or endoplasmic reticulum stress, and exhibited different responses to vitamin E than had been observed in clinical trials. Overall, patient-derived rod cells recapitulated the disease phenotype and expressed markers of cellular stresses. Our results demonstrate that the use of patient-derived iPS cells will help to elucidate the pathogenic mechanisms caused by genetic mutations in RP.
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影响因子：
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作者：
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通讯作者：
de Jong, PTVM