Directing human neural stem/precursor cells into oligodendrocytes by overexpression of Olig2 transcription factor.
Multipotential neural stem/precursor cells of the central nervous system were extensively studied for their properties of generating myelinating oligodendrocytes both in vitro and in vivo upon engraftment in animal models of myelin disorders, such as leucodystrophy and multiple sclerosis. These studies provided proof-of-principle that efficient myelination can be achieved by cell transplantation. However, one major drawback of cell-based therapy of myelin diseases is the difficulty in generating oligodendrocytes efficiently from human fetal neural stem/precursor cells (hNPC). Here we explored whether overexpression of the basic helix-loop-helix (bHLH) transcription factor Olig2 in fetal hNPC could enhance the generation of oligodendrocytes both in vitro and in vivo. We report that transduction of hNPC with Olig2-encoding lentiviral vectors enhances their commitment toward an oligodendroglial fate. Moreover, Olig2-transduced hNPC, grafted into the dysmyelinated shiverer mouse brain, survived up to 9 weeks, migrated extensively, and differentiated into MBP(+) myelinating oligodendrocytes. In contrast, control hNPC remained at a less mature stage and generated very few myelinating oligodendrocytes. Our study indicates that bHLH transcription factors, such as Olig2, are interesting targets for directing hNPC into myelinating oligodendrocytes.
Maire
Cécile L
CL
Université Pierre et Marie Curie-Paris 6, UMR S 975, Paris, France.
Buchet
Delphine
D
Kerninon
Christophe
C
Deboux
Cyrille
C
Baron-Van Evercooren
Anne
A
Nait-Oumesmar
Brahim
B
D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D016380:Brain Tissue Transplantation / Q000379:methods; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage / Q000235:genetics; D002478:Cells, Cultured; D005333:Fetus; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics / Q000494:pharmacology; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008818:Mice, Neurologic Mutants; D009186:Myelin Sheath / Q000378:metabolism / Q000648:ultrastructure; D009416:Nerve Regeneration / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D018874:Spheroids, Cellular; D033581:Stem Cell Transplantation / Q000379:methods; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D014161:Transduction, Genetic / Q000379:methods
D051792:Basic Helix-Loop-Helix Proteins; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; C405708:OLIG2 protein, human