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 journalArticleResearchpeer-review

171 Citations (Scopus)

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
Number of pages16
JournalCell Stem Cell
Volume21
Issue number3
DOIs
Publication statusPublished - 7 Sep 2017

Keywords

  • ATAC-seq
  • Brain organoid
  • Cortex
  • Fusion
  • HESC
  • Interneuron
  • MGE
  • Neuronal migration
  • Single cell RNA-seq
  • Transcriptional regulation

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