Engineering of human brain organoids with a functional vascular-like system

Bilal Cakir; Yangfei Xiang; Yoshiaki Tanaka; Mehmet H. Kural; Maxime Parent; Young Jin Kang; Kayley Chapeton; Benjamin Patterson; Yifan Yuan; Chang Shun He; Micha Sam B. Raredon; Jake Dengelegi; Kun Yong Kim; Pingnan Sun; Mei Zhong; Sangho Lee; Prabir Patra; Fahmeed Hyder; Laura E. Niklason; Sang Hun Lee; Young Sup Yoon; In Hyun Park

doi:10.1038/s41592-019-0586-5

Engineering of human brain organoids with a functional vascular-like system

Bilal Cakir, Yangfei Xiang, Yoshiaki Tanaka, Mehmet H. Kural, Maxime Parent, Young Jin Kang, Kayley Chapeton, Benjamin Patterson, Yifan Yuan, Chang Shun He, Micha Sam B. Raredon, Jake Dengelegi, Kun Yong Kim, Pingnan Sun, Mei Zhong, Sangho Lee, Prabir Patra, Fahmeed Hyder, Laura E. Niklason, Sang Hun LeeYoung Sup Yoon, In Hyun Park

Neuroscience

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

620 Scopus citations

Abstract

Human cortical organoids (hCOs), derived from human embryonic stem cells (hESCs), provide a platform to study human brain development and diseases in complex three-dimensional tissue. However, current hCOs lack microvasculature, resulting in limited oxygen and nutrient delivery to the inner-most parts of hCOs. We engineered hESCs to ectopically express human ETS variant 2 (ETV2). ETV2-expressing cells in hCOs contributed to forming a complex vascular-like network in hCOs. Importantly, the presence of vasculature-like structures resulted in enhanced functional maturation of organoids. We found that vascularized hCOs (vhCOs) acquired several blood-brain barrier characteristics, including an increase in the expression of tight junctions, nutrient transporters and trans-endothelial electrical resistance. Finally, ETV2-induced endothelium supported the formation of perfused blood vessels in vivo. These vhCOs form vasculature-like structures that resemble the vasculature in early prenatal brain, and they present a robust model to study brain disease in vitro.

Original language	English
Pages (from-to)	1169-1175
Number of pages	7
Journal	Nature Methods
Volume	16
Issue number	11
DOIs	https://doi.org/10.1038/s41592-019-0586-5
State	Published - Nov 1 2019

Bibliographical note

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.

ASJC Scopus subject areas

Biotechnology
Biochemistry
Molecular Biology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41592-019-0586-5

Cite this

Cakir, B., Xiang, Y., Tanaka, Y., Kural, M. H., Parent, M., Kang, Y. J., Chapeton, K., Patterson, B., Yuan, Y., He, C. S., Raredon, M. S. B., Dengelegi, J., Kim, K. Y., Sun, P., Zhong, M., Lee, S., Patra, P., Hyder, F., Niklason, L. E., ... Park, I. H. (2019). Engineering of human brain organoids with a functional vascular-like system. Nature Methods, 16(11), 1169-1175. https://doi.org/10.1038/s41592-019-0586-5

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title = "Engineering of human brain organoids with a functional vascular-like system",

abstract = "Human cortical organoids (hCOs), derived from human embryonic stem cells (hESCs), provide a platform to study human brain development and diseases in complex three-dimensional tissue. However, current hCOs lack microvasculature, resulting in limited oxygen and nutrient delivery to the inner-most parts of hCOs. We engineered hESCs to ectopically express human ETS variant 2 (ETV2). ETV2-expressing cells in hCOs contributed to forming a complex vascular-like network in hCOs. Importantly, the presence of vasculature-like structures resulted in enhanced functional maturation of organoids. We found that vascularized hCOs (vhCOs) acquired several blood-brain barrier characteristics, including an increase in the expression of tight junctions, nutrient transporters and trans-endothelial electrical resistance. Finally, ETV2-induced endothelium supported the formation of perfused blood vessels in vivo. These vhCOs form vasculature-like structures that resemble the vasculature in early prenatal brain, and they present a robust model to study brain disease in vitro.",

author = "Bilal Cakir and Yangfei Xiang and Yoshiaki Tanaka and Kural, {Mehmet H.} and Maxime Parent and Kang, {Young Jin} and Kayley Chapeton and Benjamin Patterson and Yifan Yuan and He, {Chang Shun} and Raredon, {Micha Sam B.} and Jake Dengelegi and Kim, {Kun Yong} and Pingnan Sun and Mei Zhong and Sangho Lee and Prabir Patra and Fahmeed Hyder and Niklason, {Laura E.} and Lee, {Sang Hun} and Yoon, {Young Sup} and Park, {In Hyun}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2019",

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doi = "10.1038/s41592-019-0586-5",

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Cakir, B, Xiang, Y, Tanaka, Y, Kural, MH, Parent, M, Kang, YJ, Chapeton, K, Patterson, B, Yuan, Y, He, CS, Raredon, MSB, Dengelegi, J, Kim, KY, Sun, P, Zhong, M, Lee, S, Patra, P, Hyder, F, Niklason, LE, Lee, SH, Yoon, YS & Park, IH 2019, 'Engineering of human brain organoids with a functional vascular-like system', Nature Methods, vol. 16, no. 11, pp. 1169-1175. https://doi.org/10.1038/s41592-019-0586-5

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T1 - Engineering of human brain organoids with a functional vascular-like system

AU - Cakir, Bilal

AU - Xiang, Yangfei

AU - Tanaka, Yoshiaki

AU - Kural, Mehmet H.

AU - Parent, Maxime

AU - Kang, Young Jin

AU - Chapeton, Kayley

AU - Patterson, Benjamin

AU - Yuan, Yifan

AU - He, Chang Shun

AU - Raredon, Micha Sam B.

AU - Dengelegi, Jake

AU - Kim, Kun Yong

AU - Sun, Pingnan

AU - Zhong, Mei

AU - Lee, Sangho

AU - Patra, Prabir

AU - Hyder, Fahmeed

AU - Niklason, Laura E.

AU - Lee, Sang Hun

AU - Yoon, Young Sup

AU - Park, In Hyun

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Human cortical organoids (hCOs), derived from human embryonic stem cells (hESCs), provide a platform to study human brain development and diseases in complex three-dimensional tissue. However, current hCOs lack microvasculature, resulting in limited oxygen and nutrient delivery to the inner-most parts of hCOs. We engineered hESCs to ectopically express human ETS variant 2 (ETV2). ETV2-expressing cells in hCOs contributed to forming a complex vascular-like network in hCOs. Importantly, the presence of vasculature-like structures resulted in enhanced functional maturation of organoids. We found that vascularized hCOs (vhCOs) acquired several blood-brain barrier characteristics, including an increase in the expression of tight junctions, nutrient transporters and trans-endothelial electrical resistance. Finally, ETV2-induced endothelium supported the formation of perfused blood vessels in vivo. These vhCOs form vasculature-like structures that resemble the vasculature in early prenatal brain, and they present a robust model to study brain disease in vitro.

AB - Human cortical organoids (hCOs), derived from human embryonic stem cells (hESCs), provide a platform to study human brain development and diseases in complex three-dimensional tissue. However, current hCOs lack microvasculature, resulting in limited oxygen and nutrient delivery to the inner-most parts of hCOs. We engineered hESCs to ectopically express human ETS variant 2 (ETV2). ETV2-expressing cells in hCOs contributed to forming a complex vascular-like network in hCOs. Importantly, the presence of vasculature-like structures resulted in enhanced functional maturation of organoids. We found that vascularized hCOs (vhCOs) acquired several blood-brain barrier characteristics, including an increase in the expression of tight junctions, nutrient transporters and trans-endothelial electrical resistance. Finally, ETV2-induced endothelium supported the formation of perfused blood vessels in vivo. These vhCOs form vasculature-like structures that resemble the vasculature in early prenatal brain, and they present a robust model to study brain disease in vitro.

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JF - Nature Methods

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Engineering of human brain organoids with a functional vascular-like system

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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