Astroglia are integral to brain development and the emergence of neurodevelopmental disorders.However,studying the pathophysiology of human astroglia using brain organoid models has been hindered by ineficient astrogl...Astroglia are integral to brain development and the emergence of neurodevelopmental disorders.However,studying the pathophysiology of human astroglia using brain organoid models has been hindered by ineficient astrogliogene-sis.In this study,we introduce a robust method for generating astroglia-enriched organoids through BMP4 treatment during the neural differentiation phase of organoid development.Our RNA sequencing analysis reveals that astroglia developed within these organoids exhibit advanced developmental characteristics and enhanced synaptic functions compared to those grown under traditional two-dimensional conditions,particularly highlighted by increased neu-rexin(NRXN)-neuroligin(NLGN)signaling.Cell adhesion molecules,such as NRXN and NLGN,are essential in regulat-ing interactions between astroglia and neurons.We further discovered that brain organoids derived from human embryonic stem cells(hESCs)harboring the autism-associated NLGN3 R451C mutation exhibit increased astroglio-genesis.Notably,the NLGN3 R451C astroglia demonstrate enhanced branching,indicating a more intricate morphol-ogy.Interestingly,our RNA sequencing data suggest that these mutant astroglia significantly upregulate pathways that support neural functions when compared to isogenic wild-type astroglia.Our findings establish a novel astroglia-enriched organoid model,offering a valuable platform for probing the roles of human astroglia in brain development and related disorders.展开更多
基金supported by grants from the NIH(R01NS102382,R01NS122108,and R01AG073779 to P.J.)M.J.was supported by a post-doctoral fellowship award from the New Jersey Department of Health(CAUT24DFP004)+1 种基金A.V.P.was supported by a graduate trainee T32 fellowship award from the Training in Translating Neuroscience to Therapies program at Rutgers University(T32NS115700)L.C.was supported by the Rutgers HealthAdvance Fund(NHLBI U01HL150852 to L.C.)。
文摘Astroglia are integral to brain development and the emergence of neurodevelopmental disorders.However,studying the pathophysiology of human astroglia using brain organoid models has been hindered by ineficient astrogliogene-sis.In this study,we introduce a robust method for generating astroglia-enriched organoids through BMP4 treatment during the neural differentiation phase of organoid development.Our RNA sequencing analysis reveals that astroglia developed within these organoids exhibit advanced developmental characteristics and enhanced synaptic functions compared to those grown under traditional two-dimensional conditions,particularly highlighted by increased neu-rexin(NRXN)-neuroligin(NLGN)signaling.Cell adhesion molecules,such as NRXN and NLGN,are essential in regulat-ing interactions between astroglia and neurons.We further discovered that brain organoids derived from human embryonic stem cells(hESCs)harboring the autism-associated NLGN3 R451C mutation exhibit increased astroglio-genesis.Notably,the NLGN3 R451C astroglia demonstrate enhanced branching,indicating a more intricate morphol-ogy.Interestingly,our RNA sequencing data suggest that these mutant astroglia significantly upregulate pathways that support neural functions when compared to isogenic wild-type astroglia.Our findings establish a novel astroglia-enriched organoid model,offering a valuable platform for probing the roles of human astroglia in brain development and related disorders.
