TY - JOUR
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
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
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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U2 - 10.1038/s41592-019-0586-5
DO - 10.1038/s41592-019-0586-5
M3 - Article
C2 - 31591580
AN - SCOPUS:85074051539
SN - 1548-7091
VL - 16
SP - 1169
EP - 1175
JO - Nature Methods
JF - Nature Methods
IS - 11
ER -