Olig2 overexpression induces the in vitro differentiation of neural stem cells into mature oligodendrocytes.
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.
Copray
Sjef
S
Department of Medical Physiology, University Medical Centre Groningen, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands. j.c.v.m.copray@med.rug.nl
Balasubramaniyan
Veerakumar
V
Levenga
Josien
J
de Bruijn
Jorick
J
Liem
Robert
R
Boddeke
Erik
E
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002454:Cell Differentiation; D002614:Chelating Agents / Q000633:toxicity; D003471:Cuprizone / Q000633:toxicity; D004195:Disease Models, Animal; D015870:Gene Expression; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008854:Microscopy, Electron; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000628:therapy; D009186:Myelin Sheath / Q000648:ultrastructure; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000166:cytology* / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D029961:Zebrafish Proteins
D051792:Basic Helix-Loop-Helix Proteins; D002614:Chelating Agents; D003471:Cuprizone; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715627:Nkx2-2 protein, mouse; C512773:Olig2 protein, mouse; C000715630:nkx2.2b protein, zebrafish