Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia.
Human iPSC Glial Mouse Chimeras Reveal Glial Contributions to Schizophrenia.
复制标题
人IPSC神经胶质小鼠嵌合体揭示了对精神分裂症的神经胶质贡献。
DOI：
10.1016/j.stem.2017.06.012
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发表时间：
2017-08-03
期刊：
影响因子：
23.9
通讯作者：
Goldman SA
中科院分区：
文献类型：
--
作者：
Windrem MS;Osipovitch M;Liu Z;Bates J;Chandler-Militello D;Zou L;Munir J;Schanz S;McCoy K;Miller RH;Wang S;Nedergaard M;Findling RL;Tesar PJ;Goldman SA
在这项研究中，我们调查是否内在胶质功能障碍有助于精神分裂症（SCZ）的发病机制。我们的方法是建立人源化胶质嵌合小鼠使用胶质祖细胞（GPCs）从诱导多能干细胞来源于儿童期发病SCZ患者。新生儿植入髓鞘缺陷性颤抖小鼠后，SCZ GPCs过早迁移到皮质，导致相对于对照组白色物质扩张减少和髓鞘形成不足。SCZ胶质细胞嵌合体也表现出延迟的星形胶质细胞分化和异常的星形胶质细胞形态。当在髓鞘野生型宿主中建立时，SCZ胶质小鼠表现出减少的前脉冲抑制和异常行为，包括过度焦虑，反社会特征和睡眠紊乱。培养的SCZ hGPCs的RNAseq显示神经胶质分化相关和突触基因表达被破坏，表明神经胶质病理是细胞自主性的。因此，我们的数据提示神经胶质成熟受损在精神分裂症的发展中起着因果作用，并为其体内评估提供了一个人源化模型。Goldman和他的同事使用与人类患者源性神经胶质祖细胞嵌合的小鼠来研究神经胶质是否与儿童期发作的精神分裂症有关。他们所看到的细胞分化、髓鞘形成和行为的缺陷强烈表明，胶质细胞实际上在这种疾病的发病机制中具有以前未被认识到的作用。
In this study, we investigated whether intrinsic glial dysfunction contributes to the pathogenesis of schizophrenia (SCZ). Our approach was to establish humanized glial chimeric mice using glial progenitor cells (GPCs) produced from induced pluripotent stem cells derived from patients with childhood-onset SCZ. After neonatal implantation into myelin-deficient shiverer mice, SCZ GPCs showed premature migration into the cortex, leading to reduced white matter expansion and hypomyelination relative to controls. The SCZ glial chimeras also showed delayed astrocytic differentiation and abnormal astrocytic morphologies. When established in myelin wild-type hosts, SCZ glial mice showed reduced prepulse inhibition and abnormal behavior, including excessive anxiety, antisocial traits and disturbed sleep. RNAseq of cultured SCZ hGPCs revealed disrupted glial differentiation-associated and synaptic gene expression, indicating that glial pathology was cell-autonomous. Our data therefore suggest a causal role for impaired glial maturation in the development of schizophrenia, and provide a humanized model for its in vivo assessment. Goldman and colleagues use mice chimerized with human patient-derived glial progenitor cells to ask whether glia contribute to childhood-onset schizophrenia. The defects in cell differentiation, myelination, and behavior that they see strongly suggest that glial cells do in fact have a previously unappreciated role in the pathogenesis of this disease.
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DOI：
10.1523/jneurosci.6000-09.2010
发表时间：
2010-03-10
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
De Biase LM;Nishiyama A;Bergles DE
通讯作者：
Bergles DE
影响因子：
--
作者：
Bergles DE;Jabs R;Steinhäuser C
通讯作者：
Steinhäuser C
影响因子：
--
作者：
Geyer, M A;Swerdlow, N R
通讯作者：
Swerdlow, N R
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
3.4
作者：
Araque, A;Parpura, V;Haydon, PG
通讯作者：
Haydon, PG