Differentiation of multipotent neural stem cells derived from Rett syndrome patients is biased toward the astrocytic lineage.
Differentiation of multipotent neural stem cells derived from Rett syndrome patients is biased toward the astrocytic lineage.
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DOI：
10.1186/s13041-015-0121-2
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发表时间：
2015-05-27
期刊：
影响因子：
3.6
通讯作者：
Okano H
中科院分区：
文献类型：
--
作者：
Andoh-Noda T;Akamatsu W;Miyake K;Matsumoto T;Yamaguchi R;Sanosaka T;Okada Y;Kobayashi T;Ohyama M;Nakashima K;Kurosawa H;Kubota T;Okano H
Rett综合征（RTT）是女性中最常见的神经发育障碍之一，由X连锁甲基CpG结合蛋白2基因（MECP 2）的从头突变引起。虽然由于突变型MeCP 2引起的神经元基因的异常调节被认为会诱导RTT患者的自闭症行为和发育受损，但异常神经进展背后的精确细胞机制仍不清楚。两组表达野生型或突变型MECP 2的人诱导多能干细胞（hiPSC）系的等基因对由单对10岁RTT-单卵（MZ）雌性双胞胎产生。表达突变体MeCP 2的hiPSC系在任何分化阶段都不表达可检测的MeCP 2蛋白。MeCP 2的缺乏反映了分化的神经细胞而不是未分化的hiPSC中改变的基因表达模式，如通过微阵列分析所评估的。此外，神经细胞谱系中的MeCP 2缺乏增加了多能神经干细胞的星形胶质细胞特异性分化。此外，染色质免疫沉淀（ChIP）和亚硫酸氢盐测序分析表明，异常的胶质细胞酸性蛋白基因（GFAP）的表达在MeCP 2阴性，分化的神经细胞由于缺乏MeCP 2结合到GFAP基因。同基因RTT-hiPSC模型证明MeCP 2参与神经细胞的分化。此外，MeCP 2缺陷触发星形胶质细胞基因表达的扰动，产生从RTT-hiPSC衍生的神经干细胞加速的星形胶质细胞形成。这些发现可能为RTT中的星形胶质细胞异常提供新的线索，并表明星形胶质细胞可能是RTT治疗的新靶点，星形胶质细胞是神经元稳态和功能所必需的。本文的在线版本（doi：10.1186/s13041-015-0121-2）包含补充材料，可供授权用户使用。
Rett syndrome (RTT) is one of the most prevalent neurodevelopmental disorders in females, caused by de novo mutations in the X-linked methyl CpG-binding protein 2 gene, MECP2. Although abnormal regulation of neuronal genes due to mutant MeCP2 is thought to induce autistic behavior and impaired development in RTT patients, precise cellular mechanisms underlying the aberrant neural progression remain unclear. Two sets of isogenic pairs of either wild-type or mutant MECP2-expressing human induced pluripotent stem cell (hiPSC) lines were generated from a single pair of 10-year-old RTT-monozygotic (MZ) female twins. Mutant MeCP2-expressing hiPSC lines did not express detectable MeCP2 protein during any stage of differentiation. The lack of MeCP2 reflected altered gene expression patterns in differentiated neural cells rather than in undifferentiated hiPSCs, as assessed by microarray analysis. Furthermore, MeCP2 deficiency in the neural cell lineage increased astrocyte-specific differentiation from multipotent neural stem cells. Additionally, chromatin immunoprecipitation (ChIP) and bisulfite sequencing assays indicated that anomalous glial fibrillary acidic protein gene (GFAP) expression in the MeCP2-negative, differentiated neural cells resulted from the absence of MeCP2 binding to the GFAP gene. An isogenic RTT-hiPSC model demonstrated that MeCP2 participates in the differentiation of neural cells. Moreover, MeCP2 deficiency triggers perturbation of astrocytic gene expression, yielding accelerated astrocyte formation from RTT-hiPSC-derived neural stem cells. These findings are likely to shed new light on astrocytic abnormalities in RTT, and suggest that astrocytes, which are required for neuronal homeostasis and function, might be a new target of RTT therapy. The online version of this article (doi:10.1186/s13041-015-0121-2) contains supplementary material, which is available to authorized users.
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