Institute of Neurosciences, The Fourth Military Medical University, Xi'an, 710032, P.R. China.
CNS Neurol Disord Drug Targets. 2011 Jun;10(4):449-58. doi: 10.2174/187152711795563994.
Parkinson's disease (PD), a common degenerative disease in humans, is known to result from loss of dopamine neurons in the substantia nigra and is characterized by severe motor symptoms of tremor, rigidity, bradykinsia and postural instability. Although levodopa administration, surgical neural lesion, and deep brain stimulation have been shown to be effective in improving parkinsonian symptoms, cell replacement therapy such as transplantation of dopamine neurons or neural stem cells has shed new light on an alternative treatment strategy for PD. While the difficulty in securing donor dopamine neurons and the immuno-rejection of neural transplants largely hinder application of neural transplants in clinical treatment, induced pluripotent stem cells (iPS cells) derived from somatic cells may represent a powerful tool for studying the pathogenesis of PD and provide a source for replacement therapies in this neurodegenerative disease. Yamanaka et al. [2006, 2007] first succeeded in generating iPS cells by reprogramming fibroblasts with four transcription factors, Oct4, Sox2, Klf4, and c-Myc in both mouse and human. Animal studies have further shown that iPS cells from fibroblasts could be induced into dopamine neurons and transplantation of these cells within the central nervous system improved motor symptoms in the 6-OHDA model of PD. More interestingly, neural stem cells or fibroblasts from patients can be efficiently reprogrammed and subsequently differentiated into dopamine neurons. Derivation of patient-specific iPS cells and subsequent differentiation into dopamine neurons would provide a disease-specific in vitro model for disease pathology, drug screening and personalized stem cell therapy for PD. This review summarizes current methods and modifications in producing iPS cells from somatic cells as well as safety concerns of reprogramming procedures. Novel reprogramming strategies that deter abnormal permanent genetic and epigenetic alterations are essential for propagating clinically-qualified iPS cells. Future investigations into cell transforming and reprogramming processes are needed to generate the disease-specific iPS cells for personalized regeneration medicine of PD patients by disclosing detailed reprogramming mechanisms.
帕金森病(PD)是一种常见的人类退行性疾病,已知其发病原因是黑质多巴胺神经元的丧失,其特征是严重的运动症状,如震颤、僵直、运动徐缓及姿势不稳。虽然左旋多巴给药、神经外科损伤和深部脑刺激已被证明可有效改善帕金森病症状,但多巴胺神经元或神经干细胞的细胞替代疗法为 PD 的替代治疗策略提供了新的思路。尽管获取供体多巴胺神经元的困难以及神经移植的免疫排斥反应在很大程度上阻碍了神经移植在临床治疗中的应用,但体细胞来源的诱导多能干细胞(iPS 细胞)可能代表了研究 PD 发病机制的有力工具,并为这种神经退行性疾病的替代治疗提供了来源。Yamanaka 等人 [2006,2007] 首次成功地通过在小鼠和人类中将四个转录因子(Oct4、Sox2、Klf4 和 c-Myc)重编程成纤维细胞而生成 iPS 细胞。动物研究进一步表明,来自成纤维细胞的 iPS 细胞可被诱导分化为多巴胺神经元,将这些细胞移植到中枢神经系统内可改善 6-OHDA 诱导的 PD 动物模型的运动症状。更有趣的是,患者的神经干细胞或成纤维细胞可被高效重编程,并随后分化为多巴胺神经元。源自患者的特异性 iPS 细胞的分化为多巴胺神经元可为疾病病理学、药物筛选和 PD 的个性化干细胞治疗提供特定疾病的体外模型。本文综述了目前从体细胞生成 iPS 细胞的方法和改良方法,以及重编程过程的安全性问题。对于产生临床上合格的 iPS 细胞而言,新型的重编程策略对于阻止异常的永久性遗传和表观遗传改变至关重要。未来需要进一步研究细胞转化和重编程过程,以揭示详细的重编程机制,从而为 PD 患者的个性化再生医学生成特定疾病的 iPS 细胞。
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