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

Research output: Contribution to journalArticlepeer-review

413 Scopus citations


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 languageEnglish
Pages (from-to)1169-1175
Number of pages7
JournalNature Methods
Issue number11
StatePublished - Nov 1 2019

Bibliographical note

Funding Information:
I.-H.P. was partly supported by the NIH (grant nos. GM111667-01, R01AA025080-01, R01CA203011-2), CSCRF (grant nos. 14-SCC-YALE-01 and 16-RMB-YALE-04), Kavli Foundation, Simons Foundation and the KRIBB/KRCF research initiative program (grant no. NAP-09-3). This work was supported by the College of Medicine, University of Arkansas for Medical Sciences to Sang-Hun Lee, the Core Facilities of the Center for Translational Neuroscience, an award (no. P30 GM110702) from the IDeA program at NIGMS. Y.-S.Y was partly supported by the NIH (grant nos. R01HL127759 and DP3DK108245) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, Republic of Korea (grant nos. HI15C2782 and HI16C2211). L.E.N was partly supported by NIH (1R21 EB024889, 1R01 HL148819), M.P. was partly supported by Fonds de recherche du Québec – Santé in Canada, and F.H. was partly supported by NIH (EB023366-02, MH067528-02). Computation time was provided by Yale University Biomedical High Performance Computing Center.

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

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Cell Biology


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