The authors would like to correct Fig.2g.An annotation error was introduced in the preparation of this figure for publication.The authors declare that this correction does not change the results or conclusions of this...The authors would like to correct Fig.2g.An annotation error was introduced in the preparation of this figure for publication.The authors declare that this correction does not change the results or conclusions of this paper.The authors sincerely apologize for having this error in the article,and apologize for any inconvenience caused.展开更多
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...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.展开更多
Early human brain development can be affected by multiple prenatal factors that involve chemical exposures in utero,maternal health characteristics such as psychiatric disorders,and cancer.Breast cancer is one of the ...Early human brain development can be affected by multiple prenatal factors that involve chemical exposures in utero,maternal health characteristics such as psychiatric disorders,and cancer.Breast cancer is one of the most common cancers worldwide arising pregnancy.However,it is not clear whether the breast cancer might influence the brain development of fetus.Exosomes secreted by breast cancer cells play a critical role in mediating intercellular communication and interplay between different organs.In this work,we engineered human induced pluripotent stem cells(hiPSCs)-derived brain organoids in an array of micropillar chip and probed the influences of breast cancer cell(MCF-7)derived-exosomes on the early neurodevelopment of brain.The formed brain organoids can recapitulate essential features of embryonic human brain at early stages,in terms of neurogenesis,forebrain regionalization,and cortical organization.Treatment with breast cancer cell derived-exosomes,brain organoids exhibited enhanced expression of stemness-related marker OCT4 and forebrain marker PAX6.RNA-seq analysis reflected several activated signaling pathways associated with breast cancer,medulloblastoma and neurogenesis in brain organoids induced by tumor-derived exosomes.These results suggested that breast cancer cell-derived exosomes might lead to the impaired neurodevelopment in the brain organoids and the carcinogenesis of brain organoids.It potentially implies the fetus of pregnant women with breast cancer has the risk of impaired neurodevelopmental disorder after birth.展开更多
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29050301,XDB32030200,and XDA16020900)the National Key R&D Program of China(2017YFB0405404)+6 种基金the National Science and Technology Major Project(2018ZX09201017-001-001)Yunnan Key Research and Development Program(202003AD150009)the National Natural Science Foundation of China(31671038,31971373,8170347081803492)China Postdoctoral Science Foundation(2019M660065)Innovation Program of Science and Research from the Dalian Institute of Chemical PhysicsChinese Academy of Sciences(DICP I201934)。
文摘The authors would like to correct Fig.2g.An annotation error was introduced in the preparation of this figure for publication.The authors declare that this correction does not change the results or conclusions of this paper.The authors sincerely apologize for having this error in the article,and apologize for any inconvenience caused.
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)+2 种基金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).
文摘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.
基金This study was supported by the National Key R&D Program of China(No.2017YFB0405404)the Strategic Priority Research Program of the Chinese Academy of Sciences(Nos.XDB32030200,XDB29050301,XDA16020900)+2 种基金National Nature Science Foundation of China(Nos.31971373,81803492)Innovation Program of Science and Research from the DICP,CAS(DICP I201934)Yunnan Key Research and Development Program(No.202003 AD150009).
文摘Early human brain development can be affected by multiple prenatal factors that involve chemical exposures in utero,maternal health characteristics such as psychiatric disorders,and cancer.Breast cancer is one of the most common cancers worldwide arising pregnancy.However,it is not clear whether the breast cancer might influence the brain development of fetus.Exosomes secreted by breast cancer cells play a critical role in mediating intercellular communication and interplay between different organs.In this work,we engineered human induced pluripotent stem cells(hiPSCs)-derived brain organoids in an array of micropillar chip and probed the influences of breast cancer cell(MCF-7)derived-exosomes on the early neurodevelopment of brain.The formed brain organoids can recapitulate essential features of embryonic human brain at early stages,in terms of neurogenesis,forebrain regionalization,and cortical organization.Treatment with breast cancer cell derived-exosomes,brain organoids exhibited enhanced expression of stemness-related marker OCT4 and forebrain marker PAX6.RNA-seq analysis reflected several activated signaling pathways associated with breast cancer,medulloblastoma and neurogenesis in brain organoids induced by tumor-derived exosomes.These results suggested that breast cancer cell-derived exosomes might lead to the impaired neurodevelopment in the brain organoids and the carcinogenesis of brain organoids.It potentially implies the fetus of pregnant women with breast cancer has the risk of impaired neurodevelopmental disorder after birth.
