Olig2 overexpression induces the in vitro differentiation of neural stem cells into mature oligodendrocytes
Olig2 overexpression induces the in vitro differentiation of neural stem cells into mature oligodendrocytes
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DOI：
10.1634/stemcells.2005-0239
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发表时间：
2006-04-01
期刊：
影响因子：
5.2
通讯作者：
Boddeke, Erik
中科院分区：
文献类型：
--
作者：
Copray, Sjef;Balasubramaniyan, Veerakumar;Boddeke, Erik
胚胎发育过程中神经干细胞向少突胶质细胞的分化诱导是局部诱导因子和细胞内转录因子之间复杂相互作用的结果。特别是在分化的早期阶段，螺旋-环-螺旋转录因子Olig 1和Olig 2已被证明对于少突胶质细胞谱系的确定至关重要。鉴于NSC作为脱髓鞘疾病（例如，多发性硬化症），需要开发体外方法来驱动骨突胶质细胞分化过程。在补充有主要的胚胎少突胶质细胞诱导因子（如Sonic hedgehog）的培养基中进行单纯培养，仅导致约10%的NSC的少突胶质细胞分化。我们以前表明，通过基因转染诱导Ofig 1表达确实可以启动NSC中少突胶质细胞分化的第一阶段，但似乎无法产生完全成熟的功能性少突胶质细胞。在这项研究中，我们转染神经干细胞分离的胚胎小鼠脑与Olig 2基因，并发现，引入过表达Olig 2可以诱导发育完全成熟的少突胶质细胞表达转录因子Nkx2.2和所有主要的髓鞘特异性蛋白。此外，Olig 2转染的神经干细胞，与未转染的神经干细胞，发展成活跃的髓鞘再生少突胶质细胞，移植到胼胝体的长期cuprizone喂养的小鼠，脱髓鞘的动物模型。我们的研究结果表明，转染编码少突胶质细胞转录因子的基因可以有效地诱导神经干细胞分化为功能性少突胶质细胞。
Differentiation induction of neural stem cells (NSCs) into oligodendrocytes during embryogenesis is the result of a complex interaction between local induction factors and intracellular transcription factors. At the early stage of differentiation, in particular, the helix-loop-helix transcription factors Olig1 and Olig2 have been shown to be essential for oligodendrocyte lineage determination. In view of the possible application of NSCs as a source for remyelinating cell transplants in demyetinating diseases (e.g., multiple sclerosis), in vitro procedures need to be developed to drive the otigodendrocyte differentiation process. Mere culture in medium supplemented with major embryonic oligodendrogenic induction factors, such as Sonic hedgehog, results in oligodendrocyte differentiation of only about 10% of NSCs. We previously showed that induction of Ofig1 expression by gene transfection could indeed initiate the first stage of oligodendrocyte differentiation in NSCs, but appeared to be unable to generate fully mature, functional oligodendrocytes. In this study, we transfected NSCs isolated from the embryonic mouse brain with the Olig2 gene and found that the introduced overexpression of Olig2 could induce the development of fully mature oligodendrocytes expressing the transcription factor Nkx2.2 and all major myelin-specific proteins. Moreover, Olig2-transfected NSCs, in contrast to nontransfected NSCs, developed into actively remyelinating oligodendrocytes; after transplantation into the corpus callosum of long-term cuprizone-fed mice, an animal model for demyelination. Our results show that transfection of genes encoding for oligodendrogenic transcription factors can be an efficient way to induce the differentiation of NSCs into functional oligodendrocytes.