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Neurodevelopmental impairment induced by prenatal valproic acid exposure shown with the human cortical organoid-on-a-chip model

查看全文 作　　者：Kangli [1,2]Cui;Yaqing [1,2]Wang;Yujuan [1,2]Zhu;Tingting [1,2]Tao;Fangchao [1,2]Yin;Yaqiong [1,2]Guo;Haitao [1,2]Liu;Fei [2]Li;Peng [1]Wang;Yuejun [2,3]Chen;Jianhua [1,2,3,4]Qin 高影响力作者 机构地区：[1]Division of Biotechnology,CAS Key Laboratory of SSAC,Dalian Institute of Chemical Physics,Chinese Academy of Sciences,457 Zhongshan Road,Dalian 116023,China;[2]University of Chinese Academy of Sciences,Beijing 100049,China;[3]CAS Center for Excellence in Brain Science and Intelligence Technology,Chinese Academy of Sciences,Shanghai 200031,China;[4]Institute for Stem Cell and Regeneration,Chinese Academy of Sciences,Beijing,China高影响力机构 出　　处：《Microsystems & Nanoengineering》索引2020年第6卷第1期,共14页高影响力期刊 基　　金：This research was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(Nos.XDB32030200,XDB29050301,XDA16020900);the National Science and Technology Major Project(No.2018ZX09201017-001-001);the National Key R&D Program of China(No.2017YFB0405400);the National Nature Science Foundation of China(Nos.31671038,31971373);the Innovation Program of Science and Research from the DICP,CAS(DICP TMSR201601). 摘　　要：Prenatal exposure to environmental insults can increase the risk of developing neurodevelopmental disorders.Administration of the antiepileptic drug valproic acid(VPA)during pregnancy is tightly associated with a high risk of neurological disorders in offspring.However,the lack of an ideal human model hinders our comprehensive understanding of the impact of VPA exposure on fetal brain development,especially in early gestation.Herein,we present the first report indicating the effects of VPA on brain development at early stages using engineered cortical organoids from human induced pluripotent stem cells(hiPSCs).Cortical organoids were generated on micropillar arrays in a controlled manner,recapitulating the critical features of human brain development during early gestation.With VPA exposure,cortical organoids exhibited neurodevelopmental dysfunction characterized by increased neuron progenitors,inhibited neuronal differentiation and altered forebrain regionalization.Transcriptome analysis showed new markedly altered genes(e.g.,KLHL1,LHX9,and MGARP)and a large number of differential expression genes(DEGs),some of which are related to autism.In particular,comparison of transcriptome data via GSEA and correlation analysis revealed the high similarity between VPA-exposed organoids with the postmortem ASD brain and autism patient-derived organoids,implying the high risk of autism with prenatal VPA exposure,even in early gestation.These new findings facilitate a better understanding of the cellular and molecular mechanisms underlying postnatal brain disorders(such as autism)with prenatal VPA exposure.This established cortical organoid-on-a-chip platform is valuable for probing neurodevelopmental disorders under environmental exposure and can be extended to applications in the study of diseases and drug testing. 关 键 词：markedly inhibited EXPOSURE
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