Directed differentiation of human pluripotent stem cells to blood-brain barrier endothelial cells.
Directed differentiation of human pluripotent stem cells to blood-brain barrier endothelial cells.
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DOI：
10.1126/sciadv.1701679
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发表时间：
2017-11
期刊：
影响因子：
13.6
通讯作者：
Palecek SP
中科院分区：
文献类型：
--
作者：
Qian T;Maguire SE;Canfield SG;Bao X;Olson WR;Shusta EV;Palecek SP
我们报告了一种将人类多能干细胞分化为脑内皮细胞的明确方法。血脑屏障（BBB）由特殊的内皮细胞组成，对神经系统健康至关重要。了解人类血脑屏障发育及其在神经系统疾病中的作用的关键工具是可靠和可扩展的功能性脑微血管内皮细胞（BMECs）来源。人类多能干细胞（hPSCs）理论上可以在体外产生无限量的任何细胞谱系，包括bmec，用于疾病建模，药物筛选和基于细胞的治疗。我们展示了一种简单的、化学定义的方法，通过关键信号通路的小分子激活，在与发育相关的过程中将hPSCs分化为bmec。首先，通过激活典型Wnt信号，诱导人造血干细胞进入中胚层。接下来，这些中胚层前体进展为内皮祖细胞，维甲酸治疗可获得bbb特异性标记物和表型。通过该方案生成的hpsc衍生的bmec具有内皮特性，包括管状形成和低密度脂蛋白摄取，以及bmec特有的外排转运蛋白活性。值得注意的是，这些细胞表现出高于3000欧姆·cm2的高跨内皮电阻。这些hpsc衍生的bmec作为一种强大的人类体外血脑屏障模型，可用于研究脑部疾病并为治疗开发提供信息。
We report a defined method for differentiating human pluripotent stem cells to brain endothelial cells. The blood-brain barrier (BBB) is composed of specialized endothelial cells that are critical to neurological health. A key tool for understanding human BBB development and its role in neurological disease is a reliable and scalable source of functional brain microvascular endothelial cells (BMECs). Human pluripotent stem cells (hPSCs) can theoretically generate unlimited quantities of any cell lineage in vitro, including BMECs, for disease modeling, drug screening, and cell-based therapies. We demonstrate a facile, chemically defined method to differentiate hPSCs to BMECs in a developmentally relevant progression via small-molecule activation of key signaling pathways. hPSCs are first induced to mesoderm commitment by activating canonical Wnt signaling. Next, these mesoderm precursors progress to endothelial progenitors, and treatment with retinoic acid leads to acquisition of BBB-specific markers and phenotypes. hPSC-derived BMECs generated via this protocol exhibit endothelial properties, including tube formation and low-density lipoprotein uptake, as well as efflux transporter activities characteristic of BMECs. Notably, these cells exhibit high transendothelial electrical resistance above 3000 ohm·cm2. These hPSC-derived BMECs serve as a robust human in vitro BBB model that can be used to study brain disease and inform therapeutic development.
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影响因子：
2.9
作者：
Belayev, L;Busto, R;Ginsberg, MD
通讯作者：
Ginsberg, MD
影响因子：
3.2
作者：
Kurz, Haymo
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Kurz, Haymo
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作者：
Dye BR;Hill DR;Ferguson MA;Tsai YH;Nagy MS;Dyal R;Wells JM;Mayhew CN;Nattiv R;Klein OD;White ES;Deutsch GH;Spence JR
通讯作者：
Spence JR
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7.3
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Hollmann EK;Bailey AK;Potharazu AV;Neely MD;Bowman AB;Lippmann ES
通讯作者：
Lippmann ES
影响因子：
4.3
作者：
Huntley MA;Bien-Ly N;Daneman R;Watts RJ
通讯作者：
Watts RJ