最新《Nature》用iPS锁上潘多拉盒子

　　

生物通报道，Sloan-kettering研究所基因组研究中心，干细胞研究中心，发育生物学研究中心的科学家在最新一期的Nature杂志上发表iPS的最新研究进展文章Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs。

 

科学家们，将一种异常疾病患者的特异性iPS细胞（诱导多能干细胞），通过体外实验，再现了该疾病的致病机制，为被打开的潘多拉盒子带来了一把可能的钥匙。

 

家族性自主神经功能障碍（FD）是一种罕见、致命的周围神经疾病，由编码在转录伸长中涉及的一个蛋白的基因IKBKAP8所发生的一个突变引起。

 

科学家们用FD患者的体细胞通过iPS诱导技术获得特异性iPS细胞（诱导多能干细胞），并将其定向分化成了所有三个胚层的细胞，包括周围神经元在内。

 

对这些特异性的iPS的基因表达分析显示，在体外实验中IKBKAP发生组织特异性误剪接，患者的神经冠前体所表达的正常IKBKAP转录水平特别低，说明这是疾病特异性的一个机制。

 

转录组分析和细胞分析表明，神经分化和迁移行为存在缺陷。

 

这项工作朝利用iPS技术生成相关人类疾病模型的方向迈出了一步，在功能分析中也朝候选药物识别的方向迈出了一步。

（生物通 小茜）

生物通推荐原文检索

Nature 461, 402-406 (17 September 2009) | doi:10.1038/nature08320; Received 30 March 2009; Accepted 28 July 2009; Published online 19 August 2009

 

Modelling pathogenesis and treatment of familial dysautonomia using patient-specific iPSCs

Gabsang Lee1, Eirini P. Papapetrou2, Hyesoo Kim1, Stuart M. Chambers1, Mark J. Tomishima1,2,3, Christopher A. Fasano1, Yosif M. Ganat1,6, Jayanthi Menon4, Fumiko Shimizu4, Agnes Viale5, Viviane Tabar2,4, Michel Sadelain2 & Lorenz Studer1,2,4

 

Developmental Biology Program,

Center for Cell Engineering,

SKI Stem Cell Research Facility,

Department of Neurosurgery,

Genomics Core Facility, Sloan-Kettering Institute, 1275 York Ave,

Weill Cornell Graduate School, New York, New York 10065, USA

Correspondence to: Lorenz Studer1,2,4 Correspondence and requests for materials should be addressed to L.S. (Email: [e-mail]).

 

【Abstract】

The isolation of human induced pluripotent stem cells (iPSCs)1, 2, 3 offers a new strategy for modelling human disease. Recent studies have reported the derivation and differentiation of disease-specific human iPSCs4, 5, 6, 7. However, a key challenge in the field is the demonstration of disease-related phenotypes and the ability to model pathogenesis and treatment of disease in iPSCs. Familial dysautonomia (FD) is a rare but fatal peripheral neuropathy, caused by a point mutation in the IKBKAP 8 gene involved in transcriptional elongation9. The disease is characterized by the depletion of autonomic and sensory neurons. The specificity to the peripheral nervous system and the mechanism of neuron loss in FD are poorly understood owing to the lack of an appropriate model system. Here we report the derivation of patient-specific FD-iPSCs and the directed differentiation into cells of all three germ layers including peripheral neurons. Gene expression analysis in purified FD-iPSC-derived lineages demonstrates tissue-specific mis-splicing of IKBKAP in vitro. Patient-specific neural crest precursors express particularly low levels of normal IKBKAP transcript, suggesting a mechanism for disease specificity. FD pathogenesis is further characterized by transcriptome analysis and cell-based assays revealing marked defects in neurogenic differentiation and migration behaviour. Furthermore, we use FD-iPSCs for validating the potency of candidate drugs in reversing aberrant splicing and ameliorating neuronal differentiation and migration. Our study illustrates the promise of iPSC technology for gaining new insights into human disease pathogenesis and treatment.