用诱导多能干细胞模拟威廉姆斯综合症。

Neurogenesis (Austin, Tex.) Pub Date : 2017-02-06 eCollection Date: 2017-01-01 DOI:10.1080/23262133.2017.1283187
Thanathom Chailangkarn, Alysson R Muotri
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摘要

诱导多能干细胞(iPSCs)的发展为研究相关细胞类型的疾病提供了前所未有的新机会。在我们最近的研究中,威廉姆斯综合征(WS)是一种罕见的遗传性神经发育障碍,由 7 号染色体上 25-28 个基因的半杂合性缺失引起。由于缺乏相关的人类细胞模型,人们对这些缺失基因对神经水平的分子和细胞表型的影响知之甚少。我们利用细胞重编程方法报道了 WS iPSC 衍生的神经祖细胞(NPCs)凋亡增加,因此倍增时间延长,而 WS 中典型的缺失基因之一 frizzled 9 的互补可以挽救这种情况。此外,WS iPSC 衍生的 CTIP2 阳性锥体神经元表现出形态学改变,包括总树突变长和树突棘数量增加。此外,WS iPSC 衍生的神经元显示出钙瞬态频率和同步活动的增加,这可能是由于树突棘和突触数量的增加。我们的工作整合了从遗传学到 WS 患者行为的跨层次数据,揭示了 WS 人类 NPCs 和神经元中改变的细胞表型,这些表型可在其他模型系统中得到验证,如活体磁共振成像(MRI)和死后脑组织。
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Modeling Williams syndrome with induced pluripotent stem cells.

The development of induced pluripotent stem cells (iPSCs) like never before has opened novel opportunity to study diseases in relevant cell types. In our recent study, Williams syndrome (WS), a rare genetic neurodevelopmental disorder, that is caused by hemizygous deletion of 25-28 genes on chromosome 7, is of interest because of its unique cognitive and social profiles. Little is known about haploinsufficiency effect of those deleted genes on molecular and cellular phenotypes at the neural level due to the lack of relevant human cellular model. Using the cellular reprogramming approach, we reported that WS iPSC-derived neural progenitor cells (NPCs) has increased apoptosis and therefore increased doubling time, which could be rescued by complementation of frizzled 9, one of the genes typically deleted in WS. Moreover, WS iPSC-derived CTIP2-positive pyramidal neurons exhibit morphologic alterations including longer total dendrites and increasing dendritic spine number. In addition, WS iPSC-derived neurons show an increase in calcium transient frequency and synchronized activity likely due to increased number of dendritic spines and synapses. Our work integrated cross-level data from genetics to behavior of WS individuals and revealed altered cellular phenotypes in WS human NPCs and neurons that could be validated in other model systems such as magnetic resonance imaging (MRI) in live subjects and postmortem brain tissues.

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