Attenuated transcriptional response to pro-inflammatory cytokines in schizophrenia hiPSC-derived neural progenitor cells.
Attenuated transcriptional response to pro-inflammatory cytokines in schizophrenia hiPSC-derived neural progenitor cells.
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DOI：
10.1016/j.bbi.2022.06.010
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发表时间：
2022-10
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人皮质NPC对IFNγ处理显示出显著的转录应答。这种反应在精神分裂症患者的皮质NPC中减弱。异常的转录反应由线粒体和突触基因驱动。皮质NPC对IL-1β处理不显示显著的转录应答。产前发育期间母体免疫激活（MIA）是精神疾病（包括精神分裂症（SZ））的环境危险因素。来自人类和动物模型研究的证据表明，母体和胎儿隔室中细胞因子水平升高是驱动这种关联的机制的重要指示。然而，MIA所带来的精神风险的易感性存在变异性，可能受遗传因素的影响。MIA如何与对SZ易感的遗传特征相互作用，在动物模型中进行测试具有挑战性。为了解决这一差距，我们研究了差异基因表达反应是否发生在前脑谱系神经祖细胞（NPC）来自人诱导多能干细胞（hiPSC）产生的三个人诊断为精神分裂症和三个健康对照。在用干扰素-γ（IFNγ; 25 ng/μl）或白细胞介素（IL）-1β（10 ng/μl）急性（24 h）处理后，我们通过RNA测序在IFNγ处理的对照系（与未处理的对照系相比）中鉴定了3380个差异表达基因（DEG），在IFNγ处理的SZ系（与未处理的SZ系相比）中鉴定了1980个DEG。在所有品系中对IFNγ显著应答的4137个基因中，1223个基因在SZ和对照品系中是共同的。对SZ系中表现出对IFNγ处理差异响应的2914个基因进行进一步的显著性检验（对IFNγ处理和SZ诊断之间的相互作用效应应用多重检验校正），产生359个通过显著性阈值的基因。经Benjamini-Hochberg校正后，IL-1β处理条件下无差异表达基因。然而，基因集富集分析显示IL-1β影响免疫功能和神经元分化。总的来说，我们的数据表明a）与对照相比，SZ NPC显示出对IFNγ处理的减弱的转录应答; B）由于NPC中IL-1β受体的低表达，NPC培养物对IL-1β的应答似乎比IFNγ低;和c）SZ系中差异调节的基因-面对细胞因子攻击-主要与线粒体，“功能丧失”，突触前和突触后基因组。我们的发现特别强调了早期突触发育在母体免疫激活和精神分裂症风险之间的关联中的作用。
Human cortical NPCs show a significant transcriptional response to IFNγ treatment. This response is attenuated in cortical NPCs from schizophrenia patients. The abnormal transcriptional response is driven by mitochondrial and synaptic genes. Cortical NPCs do not show significant transcriptional response to IL-1β treatment. Maternal immune activation (MIA) during prenatal development is an environmental risk factor for psychiatric disorders including schizophrenia (SZ). Converging lines of evidence from human and animal model studies suggest that elevated cytokine levels in the maternal and fetal compartments are an important indication of the mechanisms driving this association. However, there is variability in susceptibility to the psychiatric risk conferred by MIA, likely influenced by genetic factors. How MIA interacts with a genetic profile susceptible to SZ is challenging to test in animal models. To address this gap, we examined whether differential gene expression responses occur in forebrain-lineage neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (hiPSC) generated from three individuals with a diagnosis of schizophrenia and three healthy controls. Following acute (24 h) treatment with either interferon-gamma (IFNγ; 25 ng/μl) or interleukin (IL)-1β (10 ng/μl), we identified, by RNA sequencing, 3380 differentially expressed genes (DEGs) in the IFNγ-treated control lines (compared to untreated controls), and 1980 DEGs in IFNγ-treated SZ lines (compared to untreated SZ lines). Out of 4137 genes that responded significantly to IFNγ across all lines, 1223 were common to both SZ and control lines. The 2914 genes that appeared to respond differentially to IFNγ treatment in SZ lines were subjected to a further test of significance (multiple testing correction applied to the interaction effect between IFNγ treatment and SZ diagnosis), yielding 359 genes that passed the significance threshold. There were no differentially expressed genes in the IL-1β-treatment conditions after Benjamini-Hochberg correction. Gene set enrichment analysis however showed that IL-1β impacts immune function and neuronal differentiation. Overall, our data suggest that a) SZ NPCs show an attenuated transcriptional response to IFNγ treatment compared to controls; b) Due to low IL-1β receptor expression in NPCs, NPC cultures appear to be less responsive to IL-1β than IFNγ; and c) the genes differentially regulated in SZ lines – in the face of a cytokine challenge – are primarily associated with mitochondrial, “loss-of-function”, pre- and post-synaptic gene sets. Our findings particularly highlight the role of early synaptic development in the association between maternal immune activation and schizophrenia risk.
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影响因子：
8.8
作者：
Bhat A;Irizar H;Thygesen JH;Kuchenbaecker K;Pain O;Adams RA;Zartaloudi E;Harju-Seppänen J;Austin-Zimmerman I;Wang B;Muir R;Summerfelt A;Du XM;Bruce H;O'Donnell P;Srivastava DP;Friston K;Hong LE;Hall MH;Bramon E
通讯作者：
Bramon E
影响因子：
14.8
作者：
Aasen, Trond;Izpisua Belmonte, Juan Carlos
通讯作者：
Izpisua Belmonte, Juan Carlos
自闭症谱系障碍（ASD）、精神分裂症和双相情感障碍中全转录组异构体水平失调
影响因子：
56.9
作者：
Gandal, Michael J.;Zhang, Pan;Geschwind, Daniel H.
通讯作者：
Geschwind, Daniel H.
患者特异性诱导的多能干细胞的效用用于自闭症谱系障碍的建模。
影响因子：
3.4
作者：
Cocks, Graham;Curran, Sarah;Gami, Priya;Uwanogho, Dafe;Jeffries, Aaron R.;Kathuria, Annie;Lucchesi, Walter;Wood, Victoria;Dixon, Rosemary;Ogilvie, Caroline;Steckler, Thomas;Price, Jack
通讯作者：
Price, Jack
DOI：
10.1126/science.aag3194
发表时间：
2016-08-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Estes ML;McAllister AK
通讯作者：
McAllister AK