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TISSUE-SPECIFIC STEM CELLS

Olig2 Overexpression Induces the In Vitro Differentiation of Neural Stem Cells into Mature Oligodendrocytes

Department of Medical Physiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands

Key Words. Neural stem cells • Oligodendrocyte progenitor cells • Embryonic Olig Nkx2.2 • Transcription factor • Mouse

Correspondence: Sjef Copray, Ph.D., Department of Medical Physiology, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands. Telephone: 31-50-3632785; Fax: 31-50-3632751; e-mail: j.c.v.m.copray{at}med.rug.nl

Received May 27, 2005; accepted for publication October 17, 2005.
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 demyelinating diseases (e.g., multiple sclerosis), in vitro procedures need to be developed to drive the oligodendrocyte 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 Olig1 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 callo-sum of long-term cuprizonefed 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.

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