Hypoxia Epigenetically Confers Astrocytic Differentiation Potential on Human Pluripotent Cell-Derived Neural Precursor Cells.
Hypoxia Epigenetically Confers Astrocytic Differentiation Potential on Human Pluripotent Cell-Derived Neural Precursor Cells.
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DOI：
10.1016/j.stemcr.2017.05.001
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发表时间：
2017-06-06
影响因子：
5.9
通讯作者：
Nakashima K
中科院分区：
文献类型：
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作者：
Yasui T;Uezono N;Nakashima H;Noguchi H;Matsuda T;Noda-Andoh T;Okano H;Nakashima K
多能干细胞衍生的人类神经前体细胞（hNPCs）具有高度的神经分化倾向，但它们需要长期培养才能有效地分化为星形胶质细胞。hNPCs的这种有偏见的命运规范背后的机制仍然难以捉摸。在这里，我们发现缺氧通过表观遗传基因调控赋予hNPCs星形细胞分化潜能，这是通过缺氧诱导因子1α和Notch信号传导之间的合作实现的，伴随着典型星形细胞特异性基因胶质原纤维酸性蛋白启动子区域DNA甲基化水平的降低。此外，我们发现这种缺氧培养条件可以应用于Rett综合征患者来源的hNPCs快速生成星形胶质细胞，并且这些星形胶质细胞会损害神经元的发育。因此，我们的研究结果进一步阐明了调节hNPC分化的分子机制，并为开发治疗星形胶质细胞介导的神经系统疾病的治疗策略提供了有吸引力的工具。缺氧诱导的DNA去甲基化使hscs - npcs向星形胶质细胞分化HIF1α和Notch信号激活在这一表观遗传变化中起关键作用RTT缺氧诱导的患者来源的星形胶质细胞损害神经元发育人类多能干细胞来源的神经前体细胞（hNPCs）需要长期培养才能向星形胶质细胞分化，阻碍了人类星形胶质细胞的功能研究。Nakashima和他的同事已经开发出一种从低氧培养的hNPCs中快速诱导星形胶质细胞的方法。缺氧诱导表观遗传改变，使hNPCs分化为星形胶质细胞。它们的缺氧培养将极大地促进与疾病相关的星形胶质细胞的研究。
Human neural precursor cells (hNPCs) derived from pluripotent stem cells display a high propensity for neuronal differentiation, but they require long-term culturing to differentiate efficiently into astrocytes. The mechanisms underlying this biased fate specification of hNPCs remain elusive. Here, we show that hypoxia confers astrocytic differentiation potential on hNPCs through epigenetic gene regulation, and that this was achieved by cooperation between hypoxia-inducible factor 1α and Notch signaling, accompanied by a reduction of DNA methylation level in the promoter region of a typical astrocyte-specific gene, Glial fibrillary acidic protein. Furthermore, we found that this hypoxic culture condition could be applied to rapid generation of astrocytes from Rett syndrome patient-derived hNPCs, and that these astrocytes impaired neuronal development. Thus, our findings shed further light on the molecular mechanisms regulating hNPC differentiation and provide attractive tools for the development of therapeutic strategies for treating astrocyte-mediated neurological disorders. Hypoxia-induced DNA demethylation allows hPSC-NPCs to differentiate into astrocytes HIF1α and Notch signal activation play a critical role in this epigenetic change RTT patient-derived astrocytes induced under hypoxia impair neuronal development Human pluripotent stem cell-derived neural precursor cells (hNPCs) require long-term culturing to differentiate into astrocytes, retarding functional studies of human astrocytes. Nakashima and colleagues have developed a method for rapid induction of astrocytes from hNPCs cultured at low oxygen levels. Hypoxia induces epigenetic change, allowing hNPCs to differentiate into astrocytes. Their hypoxic culture should greatly accelerate research for disease-relevant astrocytes.