Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, Connecticut 06520, USA.
Curr Opin Neurol. 2012 Apr;25(2):125-30. doi: 10.1097/WCO.0b013e3283518226.
PURPOSE OF REVIEW: The lack of effective treatments for various neurodegenerative disorders has placed huge burdens on society. We review the current status in applying induced pluripotent stem cell (iPSC) technology for the cellular therapy, drug screening, and in-vitro modeling of neurodegenerative diseases. RECENT FINDINGS: iPSCs are generated from somatic cells by overexpressing four reprogramming factors (Oct4, Sox2, Klf4, and Myc). Like human embryonic stem cells, iPSCs have features of self-renewal and pluripotency, and allow in-vitro disease modeling, drug screening, and cell replacement therapy. Disease-specific iPSCs were derived from patients of several neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, and spinal muscular atrophy. Neurons differentiated from these iPSCs recapitulated the in-vivo phenotypes, providing platforms for drug screening. In the case of Parkinson's disease, iPSC-derived dopaminergic neurons gave positive therapeutic effect on a rodent Parkinson's disease model as a proof of principle in using iPSCs as sources of cell replacement therapy. Beyond iPSC technology, much effort is being made to generate neurons directly from dermal fibroblasts with neuron-specific transcription factors, which does not require making iPSCs as an intermediate cell type. SUMMARY: We summarize recent progress in using iPSCs for modeling the progress and treatment of neurodegenerative diseases and provide evidence for future perspectives in this field.
目的综述:各种神经退行性疾病缺乏有效治疗方法,给社会带来了巨大负担。我们综述了应用诱导多能干细胞(iPSC)技术进行神经退行性疾病的细胞治疗、药物筛选和体外建模的现状。
最新发现:iPSC 通过过表达四个重编程因子(Oct4、Sox2、Klf4 和 Myc)从体细胞中产生。与人类胚胎干细胞一样,iPSC 具有自我更新和多能性的特点,允许进行体外疾病建模、药物筛选和细胞替代治疗。几种神经退行性疾病患者的特异性 iPSC 已经被分离出来,包括帕金森病、阿尔茨海默病、肌萎缩侧索硬化症和脊髓性肌萎缩症。这些 iPSC 分化而来的神经元再现了体内表型,为药物筛选提供了平台。在帕金森病的情况下,iPSC 衍生的多巴胺能神经元在啮齿动物帕金森病模型中产生了积极的治疗效果,为使用 iPSC 作为细胞替代治疗的来源提供了原理验证。除了 iPSC 技术之外,人们还在努力直接从皮肤成纤维细胞生成具有神经元特异性转录因子的神经元,这不需要将 iPSC 作为中间细胞类型。
总结:我们总结了使用 iPSC 对神经退行性疾病的进展和治疗进行建模的最新进展,并为该领域的未来展望提供了依据。
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