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

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

Author information

1
Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA.
2
Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
3
Department of Biology, Program in Neuroscience and Behavior, Hall-Atwater Laboratory, Wesleyan University, Middletown, CT 06459, USA.
4
Department of Cell Biology, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA.
5
Murdoch Childrens Research Institute, The Royal Children's Hospital, Parkville, VIC 3052, Australia; Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3052, Australia; Department of Anatomy and Developmental Biology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, VIC 3800, Australia.
6
Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address: inhyun.park@yale.edu.

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.

KEYWORDS:

ATAC-seq; MGE; brain organoid; cortex; fusion; hESC; interneuron; neuronal migration; single cell RNA-seq; transcriptional regulation

PMID:
28757360
DOI:
10.1016/j.stem.2017.07.007
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