Department of Experimental Medical Science, Lund University, SE-221 84 Lund, Sweden.
Cell Rep. 2012 Jun 28;1(6):703-14. doi: 10.1016/j.celrep.2012.04.009. Epub 2012 May 26.
To model human neural-cell-fate specification and to provide cells for regenerative therapies, we have developed a method to generate human neural progenitors and neurons from human embryonic stem cells, which recapitulates human fetal brain development. Through the addition of a small molecule that activates canonical WNT signaling, we induced rapid and efficient dose-dependent specification of regionally defined neural progenitors ranging from telencephalic forebrain to posterior hindbrain fates. Ten days after initiation of differentiation, the progenitors could be transplanted to the adult rat striatum, where they formed neuron-rich and tumor-free grafts with maintained regional specification. Cells patterned toward a ventral midbrain (VM) identity generated a high proportion of authentic dopaminergic neurons after transplantation. The dopamine neurons showed morphology, projection pattern, and protein expression identical to that of human fetal VM cells grafted in parallel. VM-patterned but not forebrain-patterned neurons released dopamine and reversed motor deficits in an animal model of Parkinson's disease.
为了模拟人类神经细胞的命运特化并提供用于再生疗法的细胞，我们开发了一种从人类胚胎干细胞生成人类神经祖细胞和神经元的方法，该方法再现了人类胎儿大脑的发育过程。通过添加一种激活经典 WNT 信号的小分子，我们诱导了快速且高效的、剂量依赖性的区域限定的神经祖细胞特化，其范围从端脑前脑到后脑后命运。分化开始 10 天后，祖细胞可以被移植到成年大鼠纹状体，在那里它们形成富含神经元且无肿瘤的移植物，并保持区域特化。朝向腹侧中脑（VM）特征的细胞在移植后产生了很高比例的真正多巴胺能神经元。移植的多巴胺神经元表现出与平行移植的人胎儿 VM 细胞相同的形态、投射模式和蛋白表达。VM 模式化但不是前脑模式化的神经元释放多巴胺，并在帕金森病动物模型中逆转运动缺陷。
