区域性特化 hPSC 来源的类器官融合模型模拟人类大脑发育和中间神经元迁移。

Fusion of Regionally Specified hPSC-Derived Organoids Models Human Brain Development and Interneuron Migration.

机构信息

Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA.

Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.

出版信息

Cell Stem Cell. 2017 Sep 7;21(3):383-398.e7. doi: 10.1016/j.stem.2017.07.007. Epub 2017 Jul 27.

Abstract

Organoid techniques provide unique platforms to model brain development and neurological disorders. Whereas several methods for recapitulating corticogenesis have been described, a system modeling human medial ganglionic eminence (MGE) development, a critical ventral brain domain producing cortical interneurons and related lineages, has been lacking until recently. Here, we describe the generation of MGE and cortex-specific organoids from human pluripotent stem cells that recapitulate the development of MGE and cortex domains, respectively. Population and single-cell RNA sequencing (RNA-seq) profiling combined with bulk assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) analyses revealed transcriptional and chromatin accessibility dynamics and lineage relationships during MGE and cortical organoid development. Furthermore, MGE and cortical organoids generated physiologically functional neurons and neuronal networks. Finally, fusing region-specific organoids followed by live imaging enabled analysis of human interneuron migration and integration. Together, our study provides a platform for generating domain-specific brain organoids and modeling human interneuron migration and offers deeper insight into molecular dynamics during human brain development.

摘要

类器官技术为大脑发育和神经疾病的模型提供了独特的平台。尽管已经描述了几种重现皮质发生的方法,但直到最近,一种模拟人类内侧神经节隆起(MGE)发育的系统,即产生皮质中间神经元和相关谱系的关键腹侧大脑区域的系统,一直缺乏。在这里,我们描述了从人类多能干细胞中生成 MGE 和皮质特化类器官的方法,分别重现了 MGE 和皮质区域的发育。群体和单细胞 RNA 测序(RNA-seq)分析与高通量测序的转座酶可及染色质分析(ATAC-seq)相结合,揭示了 MGE 和皮质类器官发育过程中的转录和染色质可及性动态以及谱系关系。此外,MGE 和皮质类器官生成了具有生理功能的神经元和神经元网络。最后,融合区域特异性类器官并进行实时成像,使我们能够分析人类中间神经元的迁移和整合。总之,我们的研究为生成特定脑区的类器官和模拟人类中间神经元的迁移提供了一个平台,并为人类大脑发育过程中的分子动力学提供了更深入的了解。

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