Contribution of astrocytes to familial risk and clinical manifestation of schizophrenia.
Contribution of astrocytes to familial risk and clinical manifestation of schizophrenia.
复制标题
星形胶质细胞对精神分裂症家族风险和临床表现的贡献。
作者：
先前的研究表明精神分裂症（SCZ）中有几种脑细胞类型，但星形胶质细胞的遗传影响尚不清楚。考虑到它们在人类中的高度复杂性，星形胶质细胞可能是神经发育疾病（如SCZ）的关键决定因素。研究了人类诱导多能干细胞（hiPSC）衍生的星形胶质细胞在星形胶质细胞转录组学、神经元-星形胶质细胞共培养和人源化小鼠中与SCZ的高遗传风险和临床表现相关的改变，这些星形胶质细胞来自5对与SCZ不一致的单卵双胞胎和5名健康受试者。我们发现SCZ星形胶质细胞中突触功能障碍、炎症和细胞外基质成分相关的基因表达和信号通路改变，以及SCZ星形胶质细胞移植小鼠的脱髓鞘。匠心通路分析发现SCZ疾病和SCZ星形胶质细胞突触传递通路改变，最一致的发现与胶原蛋白和细胞粘附相关通路有关。对照者、患病双胞胎和未受影响的双胞胎的星形胶质细胞对谷氨酸和GABA的反应不同，并通过氯氮平治疗恢复正常。SCZ星形胶质细胞移植小鼠前脑引起小鼠脑细胞突触功能障碍和炎症通路的基因表达改变，导致认知和嗅觉功能的行为改变。与突触功能、炎症，尤其是胶原蛋白和糖蛋白6通路相关的转录组和信号通路的差异表达表明，脑内细胞外基质组成异常是SCZ病因学的关键特征之一。精神分裂症患者的hiPSC星形细胞存在转录组异常。异常信号通路与突触功能、炎症和细胞外基质有关。星形胶质细胞改变了培养的神经元和脑功能。
Previous studies have implicated several brain cell types in schizophrenia (SCZ), but the genetic impact of astrocytes is unknown. Considering their high complexity in humans, astrocytes are likely key determinants of neurodevelopmental diseases, such as SCZ. Human induced pluripotent stem cell (hiPSC)‐derived astrocytes differentiated from five monozygotic twin pairs discordant for SCZ and five healthy subjects were studied for alterations related to high genetic risk and clinical manifestation of SCZ in astrocyte transcriptomics, neuron‐astrocyte co‐cultures, and in humanized mice. We found gene expression and signaling pathway alterations related to synaptic dysfunction, inflammation, and extracellular matrix components in SCZ astrocytes, and demyelination in SCZ astrocyte transplanted mice. While Ingenuity Pathway Analysis identified SCZ disease and synaptic transmission pathway changes in SCZ astrocytes, the most consistent findings were related to collagen and cell adhesion associated pathways. Neuronal responses to glutamate and GABA differed between astrocytes from control persons, affected twins, and their unaffected co‐twins and were normalized by clozapine treatment. SCZ astrocyte cell transplantation to the mouse forebrain caused gene expression changes in synaptic dysfunction and inflammation pathways of mouse brain cells and resulted in behavioral changes in cognitive and olfactory functions. Differentially expressed transcriptomes and signaling pathways related to synaptic functions, inflammation, and especially collagen and glycoprotein 6 pathways indicate abnormal extracellular matrix composition in the brain as one of the key characteristics in the etiology of SCZ. hiPSC astrocytes from patients with schizophrenia have abnormal transcriptome. Aberrant signaling pathways were related to synaptic functions, inflammation, and extracellular matrix. Astrocytes altered both cultured neuronal and brain functions.
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DOI：
10.1083/jcb.201509085
发表时间：
2016-03-14
期刊：
The Journal of cell biology
影响因子：
--
作者：
Su J;Chen J;Lippold K;Monavarfeshani A;Carrillo GL;Jenkins R;Fox MA
通讯作者：
Fox MA
影响因子：
7.7
作者：
Skene, Nathan G.;Roy, Marcia;Grant, Seth G. N.
通讯作者：
Grant, Seth G. N.
影响因子：
11
作者：
Gray, A. L.;Hyde, T. M.;Sodhi, M. S.
通讯作者：
Sodhi, M. S.
影响因子：
6.1
作者：
Gonzalez-Penas, Javier;Costas, Javier;Xu, Bin
通讯作者：
Xu, Bin
影响因子：
8.8
作者：
Liu, Zhengshan;Osipovitch, Mikhail;Goldman, Steven A.
通讯作者：
Goldman, Steven A.