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

doi:10.1016/j.stem.2017.07.007

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

Anatomy & Developmental Biology

Research output: Contribution to journal › Article › Research › peer-review

494 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 language	English
Pages (from-to)	383-398
Number of pages	16
Journal	Cell Stem Cell
Volume	21
Issue number	3
DOIs	https://doi.org/10.1016/j.stem.2017.07.007
Publication status	Published - 7 Sept 2017

Keywords

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

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10.1016/j.stem.2017.07.007

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Xiang, Y., Tanaka, Y., Patterson, B., Kang, Y. J., Govindaiah, G., Roselaar, N., Cakir, B., Kim, K. Y., Lombroso, A. P., Hwang, S. M., Zhong, M., Stanley, E. G., Elefanty, A. G., Naegele, J. R., Lee, S. H., Weissman, S. M., & Park, I.-H. (2017). Fusion of Regionally Specified hPSC-Derived Organoids Models Human Brain Development and Interneuron Migration. Cell Stem Cell, 21(3), 383-398. https://doi.org/10.1016/j.stem.2017.07.007

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title = "Fusion of Regionally Specified hPSC-Derived Organoids Models Human Brain Development and Interneuron Migration",

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.",

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

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Xiang, Y, Tanaka, Y, Patterson, B, Kang, YJ, Govindaiah, G, Roselaar, N, Cakir, B, Kim, KY, Lombroso, AP, Hwang, SM, Zhong, M, Stanley, EG, Elefanty, AG, Naegele, JR, Lee, SH, Weissman, SM & Park, I-H 2017, 'Fusion of Regionally Specified hPSC-Derived Organoids Models Human Brain Development and Interneuron Migration', Cell Stem Cell, vol. 21, no. 3, pp. 383-398. https://doi.org/10.1016/j.stem.2017.07.007

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T1 - Fusion of Regionally Specified hPSC-Derived Organoids Models Human Brain Development and Interneuron Migration

AU - Xiang, Yangfei

AU - Tanaka, Yoshiaki

AU - Patterson, Benjamin

AU - Kang, Young Jin

AU - Govindaiah, Gubbi

AU - Roselaar, Naomi

AU - Cakir, Bilal

AU - Kim, Kun Yong

AU - Lombroso, Adam P.

AU - Hwang, Sung Min

AU - Zhong, Mei

AU - Stanley, Edouard G.

AU - Elefanty, Andrew G.

AU - Naegele, Janice R.

AU - Lee, Sang Hun

AU - Weissman, Sherman M.

AU - Park, In-Hyun

PY - 2017/9/7

Y1 - 2017/9/7

N2 - 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.

AB - 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.

KW - ATAC-seq

KW - Brain organoid

KW - Cortex

KW - Fusion

KW - HESC

KW - Interneuron

KW - MGE

KW - Neuronal migration

KW - Single cell RNA-seq

KW - Transcriptional regulation

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SN - 1934-5909

VL - 21

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EP - 398

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 3

ER -

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

Abstract

Keywords

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