Cakir et al., Nature Method, 2019
Engineering of human brain organoids with a functional vascular-like system
Bilal Cakir # 1, Yangfei Xiang # 1, Yoshiaki Tanaka 1, Mehmet H Kural 2, Maxime Parent 3, Young-Jin Kang 4 5, Kayley Chapeton 6, Benjamin Patterson 1, Yifan Yuan 2, Chang-Shun He 7, Micha Sam B Raredon 2 7, Jake Dengelegi 8, Kun-Yong Kim 1, Pingnan Sun 1, Mei Zhong 9, Sangho Lee 10, Prabir Patra 1 8, Fahmeed Hyder 3 7, Laura E Niklason 2 7, Sang-Hun Lee 4 5, Young-Sup Yoon 10 11, In-Hyun Park 12Affiliations expand
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.