Embryonic Stem Cells Neural Differentiation Qualifies the Role of Wnt/β-Catenin Signals in Human Telencephalic Specification and Regionalization
Embryonic Stem Cells Neural Differentiation Qualifies the Role of Wnt/β-Catenin Signals in Human Telencephalic Specification and Regionalization
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DOI：
10.1002/stem.1462
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发表时间：
2013-09-01
期刊：
影响因子：
5.2
通讯作者：
Perrier, Anselme L.
中科院分区：
文献类型：
--
作者：
Nicoleau, Camille;Varela, Christine;Perrier, Anselme L.
Wnt-配体是介导哺乳动物发育中大脑前部区域图案化的关键形态原之一。我们使用人多能干细胞（hPSC）鉴定了Wnt信号在人端脑的区域特异性和次区域组织中的作用。使用SMAD抑制剂的hPSC的一步神经转化导致具有默认吻侧身份的祖细胞。这为研究Wnt信号在前后突和背腹突中的作用提供了理想的生物学底物。将hPSC-神经衍生物与Wnt-拮抗剂单独或与音刺猬（Shh）组合，我们发现Wnt-抑制以剂量依赖性方式促进端脑神经前体的端脑特化和腹侧图案化。使用最佳的Wnt-拮抗剂和Shh-激动剂信号，我们产生了人类腹侧-端脑前体，致力于分化成纹状体投射神经元在体外和体内后，同型移植在喹啉损伤的大鼠。这项研究表明，顺序组织的Wnt信号发挥了关键作用，在人类腹侧端脑领土的纹状体出现的发展。此外，本文所述的hPSC衍生的纹状体细胞的优化生产为探索和治疗亨廷顿病提供了相关的生物资源。干细胞2013;31：1763-1774
Wnt-ligands are among key morphogens that mediate patterning of the anterior territories of the developing brain in mammals. We qualified the role of Wnt-signals in regional specification and subregional organization of the human telencephalon using human pluripotent stem cells (hPSCs). One step neural conversion of hPSCs using SMAD inhibitors leads to progenitors with a default rostral identity. It provides an ideal biological substrate for investigating the role of Wnt signaling in both anteroposterior and dorso-ventral processes. Challenging hPSC-neural derivatives with Wnt-antagonists, alone or combined with sonic hedgehog (Shh), we found that Wnt-inhibition promote both telencephalic specification and ventral patterning of telencephalic neural precursors in a dose-dependent manner. Using optimal Wnt-antagonist and Shh-agonist signals we produced human ventral-telencephalic precursors, committed to differentiation into striatal projection neurons both in vitro and in vivo after homotypic transplantation in quinolinate-lesioned rats. This study indicates that sequentially organized Wnt-signals play a key role in the development of human ventral telencephalic territories from which the striatum arise. In addition, the optimized production of hPSC-derived striatal cells described here offers a relevant biological resource for exploring and curing Huntington disease. Stem Cells2013;31:1763-1774