Direct Conversion of Fibroblasts into Stably Expandable Neural Stem Cells
Direct Conversion of Fibroblasts into Stably Expandable Neural Stem Cells
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DOI：
10.1016/j.stem.2012.03.003
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发表时间：
2012-04-06
期刊：
影响因子：
23.9
通讯作者：
Edenhofer, Frank
中科院分区：
文献类型：
--
作者：
Thier, Marc;Woersdoerfer, Philipp;Edenhofer, Frank
最近的进展表明，直接诱导神经干细胞（NSCs）可以为体细胞组织或多能细胞的衍生提供另一种选择。在这里，我们展示了从小鼠成纤维细胞通过精简版本的重编程到多能性直接衍生出稳定可扩展的NSCs。通过组成性诱导Sox2、Klf4和c-Myc，同时严格将Oct4活性限制在重编程的初始阶段，我们产生了神经球样菌落，可以扩增超过50代，并且不依赖于重编程因子的持续表达。这些诱导神经干细胞（iNSCs）一致表现出NSCs的形态学和分子特征，如Nestin、Pax6和Olig2的表达，并且具有与脑源性NSCs相似的全基因组转录谱。此外，iNSCs可以分化为神经元、星形胶质细胞和少突胶质细胞。我们的研究结果表明，功能性NSCs可以通过因子驱动诱导从体细胞中生成。
Recent advances have suggested that direct induction of neural stem cells (NSCs) could provide an alternative to derivation from somatic tissues or pluripotent cells. Here we show direct derivation of stably expandable NSCs from mouse fibroblasts through a curtailed version of reprogramming to pluripotency. By constitutively inducing Sox2, Klf4, and c-Myc while strictly limiting Oct4 activity to the initial phase of reprogramming, we generated neurosphere-like colonies that could be expanded for more than 50 passages and do not depend on sustained expression of the reprogramming factors. These induced neural stem cells (iNSCs) uniformly display morphological and molecular features of NSCs, such as the expression of Nestin, Pax6, and Olig2, and have a genome-wide transcriptional profile similar to that of brain-derived NSCs. Moreover, iNSCs can differentiate into neurons, astrocytes, and oligodendrocytes. Our results demonstrate that functional NSCs can be generated from somatic cells by factor-driven induction.