Modeling autosomal dominant optic atrophy using induced pluripotent stem cells and identifying potential therapeutic targets.
Modeling autosomal dominant optic atrophy using induced pluripotent stem cells and identifying potential therapeutic targets.
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DOI：
10.1186/s13287-015-0264-1
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发表时间：
2016-01-07
影响因子：
7.5
通讯作者：
Huang T
中科院分区：
文献类型：
--
作者：
Chen J;Riazifar H;Guan MX;Huang T
许多视网膜变性疾病是由视网膜神经节细胞（RGC）的丧失引起的。常染色体显性遗传性视神经萎缩是最常见的遗传性视神经萎缩疾病，其特征是中心视力丧失和视网膜节细胞变性。目前，对这类疾病没有有效的治疗方法。然而，干细胞疗法在替代患者丢失的RGC方面具有巨大的潜力。与胚胎干细胞相比，诱导多能干细胞（iPSC）可以来源于成体体细胞，并且它们与较少的伦理问题相关，并且不太容易发生免疫排斥反应。此外，患者来源的iPSC可以为我们提供研究视神经萎缩的发病机制和潜在治疗药物的细胞模型。在这项研究中，iPSC从携带OPA 1突变（OPA 1 +/−-iPSC）的患者中获得，这些患者被诊断患有视神经萎缩。将这些iPSC分化为推定的RGC，随后通过使用RGC特异性表达标记物BRN 3a和ISLET-1对其进行表征。突变体OPA 1 +/−-iPSC表现出明显更多的凋亡，并且不能有效地分化为RGC。然而，通过添加神经诱导培养基、Noggin或雌激素，OPA 1 +/−-iPSC分化为RGC得到促进。我们的研究结果表明，OPA 1突变介导的细胞凋亡在视神经萎缩的发病机制中起着重要作用，noggin和β-雌激素可能是OPA 1相关视神经萎缩的潜在治疗药物。本文的在线版本（doi：10.1186/s13287-015-0264-1）包含补充材料，可供授权用户使用。
Many retinal degenerative diseases are caused by the loss of retinal ganglion cells (RGCs). Autosomal dominant optic atrophy is the most common hereditary optic atrophy disease and is characterized by central vision loss and degeneration of RGCs. Currently, there is no effective treatment for this group of diseases. However, stem cell therapy holds great potential for replacing lost RGCs of patients. Compared with embryonic stem cells, induced pluripotent stem cells (iPSCs) can be derived from adult somatic cells, and they are associated with fewer ethical concerns and are less prone to immune rejection. In addition, patient-derived iPSCs may provide us with a cellular model for studying the pathogenesis and potential therapeutic agents for optic atrophy. In this study, iPSCs were obtained from patients carrying an OPA1 mutation (OPA1+/−-iPSC) that were diagnosed with optic atrophy. These iPSCs were differentiated into putative RGCs, which were subsequently characterized by using RGC-specific expression markers BRN3a and ISLET-1. Mutant OPA1+/−-iPSCs exhibited significantly more apoptosis and were unable to efficiently differentiate into RGCs. However, with the addition of neural induction medium, Noggin, or estrogen, OPA1+/−-iPSC differentiation into RGCs was promoted. Our results suggest that apoptosis mediated by OPA1 mutations plays an important role in the pathogenesis of optic atrophy, and both noggin and β-estrogen may represent potential therapeutic agents for OPA1-related optic atrophy. The online version of this article (doi:10.1186/s13287-015-0264-1) contains supplementary material, which is available to authorized users.