Engineering of human brain organoids with a functional vascular-like system
Engineering of human brain organoids with a functional vascular-like system
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DOI：
10.1038/s41592-019-0586-5
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发表时间：
2019-11-01
期刊：
影响因子：
48
通讯作者：
Park, In-Hyun
中科院分区：
文献类型：
--
作者：
Cakir, Bilal;Xiang, Yangfei;Park, In-Hyun
人类皮质类器官(HCOs)来源于人类胚胎干细胞(HESCs)，为在复杂的三维组织中研究人脑发育和疾病提供了平台。然而，目前的HCOs缺乏微血管，导致向HCOs最内侧部分的氧气和养分输送有限。我们改造hESCs以异位表达人ETS变异体2(ETV2)。HCOs中表达ETV2的细胞有助于在HCOs中形成复杂的血管样网络。重要的是，血管样结构的存在增强了类器官的功能成熟。我们发现，血管化的HCOs(VhCOs)获得了几个血脑屏障的特征，包括紧密连接、营养转运体和跨内皮电阻的表达增加。最后，ETV2诱导的内皮支持体内灌流血管的形成。这些vhCO形成血管系统样结构，类似于早期产前脑中的血管系统，它们为体外研究脑疾病提供了一个强大的模型。
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.