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

Yangfei Xiang, Yoshiaki Tanaka, Benjamin Patterson, Young Jin Kang, Gubbi Govindaiah, Naomi Roselaar, Bilal Cakir, Kun Yong Kim, Adam P. Lombroso, Sung Min Hwang, Mei Zhong, Edouard G. Stanley, Andrew G. Elefanty, Janice R. Naegele, Sang Hun Lee, Sherman M. Weissman, In Hyun Park

Research output: Contribution to journalArticlepeer-review

320 Scopus citations

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. Xiang and colleagues report a method for generating human medial ganglionic eminence (MGE)-like organoids (hMGEOs) and cortical-like organoids (hCOs), which resemble the developing human MGE and cortex, respectively. By fusing hMGEOs and hCOs, they establish a 3D model to investigate human interneuron migration.

Original languageEnglish
Pages (from-to)383-398.e7
JournalCell Stem Cell
Volume21
Issue number3
DOIs
StatePublished - Sep 7 2017

Bibliographical note

Funding Information:
We thank Dr. Stewart A. Anderson for sharing MGE derivation protocol and Guilin Wang for Chromium service. I.-H.P. was partly supported by NIH (GM0099130-01 and GM111667-01), CSCRF (12-SCB-YALE-11 and 13-SCB-YALE-06), KRIBB/KRCF research initiative program (NAP-09-3), and CTSA grant UL1 RR025750 from the National Center for Advancing Translational Science (NCATS), a component of the NIH, and NIH roadmap for Medical Research. This paper's contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH. This work was also supported by the College of Medicine, University of Arkansas for Medical Sciences (startup funding to S.-H.L.) and Core Facilities of the Center for Translational Neuroscience, award P30GM110702, from the IDeA program at NIGMS. A.E. and E.G.S. are supported by research fellowships from the NHMRC (GNT1117596 and GNT1079004). Computation time was provided by Yale University Biomedical High Performance Computing Center.

Funding Information:
We thank Dr. Stewart A. Anderson for sharing MGE derivation protocol and Guilin Wang for Chromium service. I.-H.P. was partly supported by NIH  ( GM0099130-01 and GM111667-01 ), CSCRF ( 12-SCB-YALE-11 and 13-SCB-YALE-06 ), KRIBB/KRCF research initiative program ( NAP-09-3 ), and CTSA grant UL1 RR025750 from the National Center for Advancing Translational Science (NCATS ), a component of the NIH , and NIH roadmap for Medical Research . This paper’s contents are solely the responsibility of the authors and do not necessarily represent the official view of NIH. This work was also supported by the College of Medicine, University of Arkansas for Medical Sciences (startup funding to S.-H.L.) and Core Facilities of the Center for Translational Neuroscience , award P30GM110702 , from the IDeA program at NIGMS . A.E. and E.G.S. are supported by research fellowships from the NHMRC ( GNT1117596 and GNT1079004 ). Computation time was provided by Yale University Biomedical High Performance Computing Center.

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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