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

被引：645

作者：

Cakir, Bilal ^{[1
]}

Xiang, Yangfei ^{[1
]}

Tanaka, Yoshiaki ^{[1
]}

Kural, Mehmet H. ^{[2
]}

Parent, Maxime ^{[3
]}

Kang, Young-Jin ^{[4
,5
]}

Chapeton, Kayley ^{[6
]}

Patterson, Benjamin ^{[1
]}

Yuan, Yifan ^{[2
]}

He, Chang-Shun ^{[7
]}

Raredon, Micha Sam B. ^{[2
,7
]}

Dengelegi, Jake ^{[8
]}

Kim, Kun-Yong ^{[1
]}

Sun, Pingnan ^{[1
]}

Zhong, Mei ^{[9
]}

Lee, Sangho ^{[10
]}

Patra, Prabir ^{[1
,8
]}

Hyder, Fahmeed ^{[3
,7
]}

Niklason, Laura E. ^{[2
,7
]}

Lee, Sang-Hun ^{[4
,5
]}

Yoon, Young-Sup ^{[10
,11
]}

Park, In-Hyun ^{[1
]}

机构：

[1] Yale Sch Med, Dept Genet, Yale Stem Cell Ctr, New Haven, CT USA

[2] Yale Sch Med, Dept Anesthesiol, New Haven, CT USA

[3] Yale Sch Med, Dept Radiol & Biomed Imaging, New Haven, CT USA

[4] Univ Arkansas Med Sci, Dept Neurol, Little Rock, AR 72205 USA

[5] Univ Kentucky, Coll Med, Dept Neurosci, Lexington, KY USA

[6] Univ Bridgeport, Dept Elect Engn, Bridgeport, CT USA

[7] Yale Univ, Dept Biomed Engn, New Haven, CT USA

[8] Univ Bridgeport, Dept Biomed Engn, Bridgeport, CT USA

[9] Yale Sch Med, Dept Cell Biol, Yale Stem Cell Ctr, New Haven, CT USA

[10] Emory Univ, Dept Med, Div Cardiol, Atlanta, GA 30322 USA

[11] Yonsei Univ, Coll Med, Severance Biomed Sci Inst, Seoul, South Korea

来源：

NATURE METHODS | 2019年 / 16卷 / 11期

关键词：

CEREBRAL ORGANOIDS; ENDOTHELIAL-CELLS; IN-VITRO; BARRIER; MODELS; NEUROGENESIS; MAINTENANCE; GENERATION; DERIVATION; DIVERSITY;

D O I：

10.1038/s41592-019-0586-5

中图分类号：

Q5 [生物化学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1169 / +

页数：9

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