Impaired neural differentiation of induced pluripotent stem cells generated from a mouse model of Sandhoff disease.
Impaired neural differentiation of induced pluripotent stem cells generated from a mouse model of Sandhoff disease.
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DOI：
10.1371/journal.pone.0055856
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Oishi K
中科院分区：
文献类型：
--
作者：
Ogawa Y;Tanaka M;Tanabe M;Suzuki T;Togawa T;Fukushige T;Kanekura T;Sakuraba H;Oishi K
山德霍夫病（SD）是一种鞘糖脂贮积病，由Hexb基因突变引起，导致β-氨基己糖苷酶活性缺乏。这种缺乏导致神经节苷脂GM 2和相关糖脂的异常溶酶体蓄积，以及中枢神经系统的进行性恶化。糖脂储存功能障碍通过一种知之甚少的致病机制引起严重的神经退行性变。诱导多能干细胞（iPSC）技术为阐明疾病的发病机制和开发基于干细胞的疗法提供了新的机会。在这里，我们报告了从SD小鼠模型中产生疾病特异性iPSCs。这些小鼠模型衍生的iPSC（SD-iPSC）表现出多能干细胞特性和GM 2神经节苷脂的显著积累。在使用基质细胞衍生的诱导活性方法的谱系定向分化研究中，SD-iPSC显示分化为早期神经前体的能力受损。此外，SD-iPSC中从神经前体分化的神经元比野生型的情况少。SD-iPSC中Hexb基因的恢复改善了神经元分化的这种损害。这些结果为理解SD复杂的致病机制提供了新的见解。
Sandhoff disease (SD) is a glycosphingolipid storage disease that arises from mutations in the Hexb gene and the resultant deficiency in β-hexosaminidase activity. This deficiency results in aberrant lysosomal accumulation of the ganglioside GM2 and related glycolipids, and progressive deterioration of the central nervous system. Dysfunctional glycolipid storage causes severe neurodegeneration through a poorly understood pathogenic mechanism. Induced pluripotent stem cell (iPSC) technology offers new opportunities for both elucidation of the pathogenesis of diseases and the development of stem cell-based therapies. Here, we report the generation of disease-specific iPSCs from a mouse model of SD. These mouse model-derived iPSCs (SD-iPSCs) exhibited pluripotent stem cell properties and significant accumulation of GM2 ganglioside. In lineage-directed differentiation studies using the stromal cell-derived inducing activity method, SD-iPSCs showed an impaired ability to differentiate into early stage neural precursors. Moreover, fewer neurons differentiated from neural precursors in SD-iPSCs than in the case of the wild type. Recovery of the Hexb gene in SD-iPSCs improved this impairment of neuronal differentiation. These results provide new insights as to understanding the complex pathogenic mechanisms of SD.
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影响因子：
21.3
作者：
Kolev, Vihren;Mandinova, Anna;Guinea-Viniegra, Juan;Hu, Bing;Lefort, Karine;Lambertini, Chiara;Neel, Victor;Dummer, Reinhard;Wagner, Erwin F.;Dotto, G. Paolo
通讯作者：
Dotto, G. Paolo
影响因子：
4.8
作者：
Miljan, EA;Meuillet, EJ;Bremer, EG
通讯作者：
Bremer, EG
影响因子：
3.5
作者：
Huang, JQ;Trasler, JM;Gravel, RA
通讯作者：
Gravel, RA
影响因子：
16.2
作者：
Hirabayashi, Yusuke;Suzki, Nao;Gotoh, Yukiko
通讯作者：
Gotoh, Yukiko
影响因子：
46.9
作者：
Mohammad, Helai P.;Baylin, Stephen B.
通讯作者：
Baylin, Stephen B.