Spatiotemporal Recapitulation of Central Nervous System Development by Murine Embryonic Stem Cell-Derived Neural Stem/Progenitor Cells
Spatiotemporal Recapitulation of Central Nervous System Development by Murine Embryonic Stem Cell-Derived Neural Stem/Progenitor Cells
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DOI：
10.1634/stemcells.2008-0293
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发表时间：
2008-01-01
期刊：
影响因子：
5.2
通讯作者：
Okano, Hideyuki
中科院分区：
文献类型：
--
作者：
Okada, Yohei;Matsumoto, Arifumi;Okano, Hideyuki
神经干/祖细胞（NS/PC）可以产生多种神经细胞。然而，他们的命运通常受到限制，具体取决于 NS/PC 起源的时间和地点。在这里，我们证明，我们可以通过使用基于神经球的胚胎干（ES）细胞衍生的 NS/PC 培养系统来概括体外中枢神经系统（CNS）发育的时空调节。这种 ES 细胞衍生的神经球系统能够有效衍生出具有早期时间同一性和高细胞命运可塑性的高度神经源性成纤维细胞生长因子响应的 NS/PC。经过重复传代，这些 NS/PC 表现出时间进展，成为具有晚期时间特性的表皮生长因子响应性胶质生成 NS/PC；这种变化伴随着神经胶质原纤维酸性蛋白启动子表观遗传状态的改变，类似于在发育中的大脑中观察到的情况。此外，NS/PC 的头尾和背腹空间特征可以通过连续施用几种形态发生素来成功调节。这些 NS/PC 可以分化为早期出生的投射神经元，包括胆碱能神经元、儿茶酚胺能神经元、血清素能神经元和运动神经元，在体外表现出动作电位。最后，这些 NS/PC 分化为神经元，在移植到野生型和疾病模型动物中后与宿主神经元形成突触接触。因此，该培养系统可用于从ES细胞中获取特定的神经元，是研究中枢神经系统发育的潜在机制的简单而强大的工具，并且适用于神经系统疾病的再生治疗。干细胞 2008；26:3086-3098
Neural stem/progenitor cells (NS/PCs) can generate a wide variety of neural cells. However, their fates are generally restricted, depending on the time and location of NS/PC origin. Here we demonstrate that we can recapitulate the spatiotemporal regulation of central nervous system (CNS) development in vitro by using a neurosphere-based culture system of embryonic stem (ES) cell-derived NS/PCs. This ES cell-derived neurosphere system enables the efficient derivation of highly neurogenic fibroblast growth factor-responsive NS/PCs with early temporal identities and high cell-fate plasticity. Over repeated passages, these NS/PCs exhibit temporal progression, becoming epidermal growth factor-responsive gliogenic NS/PCs with late temporal identities; this change is accompanied by an alteration in the epigenetic status of the glial fibrillary acidic protein promoter, similar to that observed in the developing brain. Moreover, the rostrocaudal and dorsoventral spatial identities of the NS/PCs can be successfully regulated by sequential administration of several morphogens. These NS/PCs can differentiate into early-born projection neurons, including cholinergic, catecholaminergic, serotonergic, and motor neurons, that exhibit action potentials in vitro. Finally, these NS/PCs differentiate into neurons that form synaptic contacts with host neurons after their transplantation into wild-type and disease model animals. Thus, this culture system can be used to obtain specific neurons from ES cells, is a simple and powerful tool for investigating the underlying mechanisms of CNS development, and is applicable to regenerative treatment for neurological disorders. STEM CELLS 2008;26:3086-3098