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.

[1]  G. Comi,et al.  Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism , 2005, Nature.

[2]  D. Loy,et al.  Endogenous Nkx2.2+/Olig2+ oligodendrocyte precursor cells fail to remyelinate the demyelinated adult rat spinal cord in the absence of astrocytes , 2005, Experimental Neurology.

[3]  M. Qiu,et al.  Induction of Oligodendrocytes From Adult Human Olfactory Epithelial‐Derived Progenitors by Transcription Factors , 2005, Stem cells.

[4]  Q. Lu,et al.  Myelinogenesis and Axonal Recognition by Oligodendrocytes in Brain Are Uncoupled in Olig1-Null Mice , 2005, The Journal of Neuroscience.

[5]  V. Balasubramaniyan,et al.  Transient Expression of Olig1 Initiates the Differentiation of Neural Stem Cells into Oligodendrocyte Progenitor Cells , 2004, Stem cells.

[6]  S. Chandran,et al.  Differential generation of oligodendrocytes from human and rodent embryonic spinal cord neural precursors , 2004, Glia.

[7]  G. Martino,et al.  Cell-based remyelinating therapies in multiple sclerosis: evidence from experimental studies , 2004, Current opinion in neurology.

[8]  J. Goldman,et al.  Oligodendrocytes and progenitors become progressively depleted within chronically demyelinated lesions. , 2004, The American journal of pathology.

[9]  Angelo L. Vescovi,et al.  Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis , 2003, Nature.

[10]  A. Benraiss,et al.  Progenitor cells derived from the adult human subcortical white matter disperse and differentiate as oligodendrocytes within demyelinated lesions of the rat brain , 2002, Journal of neuroscience research.

[11]  J. Kocsis,et al.  Remyelination of the spinal cord following intravenous delivery of bone marrow cells , 2002, Glia.

[12]  J. Kocsis,et al.  Remyelination of the Rat Spinal Cord by Transplantation of Identified Bone Marrow Stromal Cells , 2002, The Journal of Neuroscience.

[13]  Robert H Miller.  Regulation of oligodendrocyte development in the vertebrate CNS , 2002, Progress in Neurobiology.

[14]  D. Rowitch,et al.  An ‘oligarchy’ rules neural development , 2002, Trends in Neurosciences.

[15]  Y. Nabeshima,et al.  The Basic Helix-Loop-Helix Factor Olig2 Is Essential for the Development of Motoneuron and Oligodendrocyte Lineages , 2002, Current Biology.

[16]  A. Kho,et al.  Identification of genes expressed with temporal-spatial restriction to developing cerebellar neuron precursors by a functional genomic approach , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Tao Sun,et al.  Common Developmental Requirement for Olig Function Indicates a Motor Neuron/Oligodendrocyte Connection , 2002, Cell.

[18]  J. Grinspan.  Cells and Signaling in Oligodendrocyte Development , 2002, Journal of neuropathology and experimental neurology.

[19]  C. Cepko,et al.  Ectopic expression of Olig1 promotes oligodendrocyte formation and reduces neuronal survival in developing mouse cortex , 2001, Nature Neuroscience.

[20]  David J. Anderson,et al.  The bHLH Transcription Factor Olig2 Promotes Oligodendrocyte Differentiation in Collaboration with Nkx2.2 , 2001, Neuron.

[21]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[22]  J. Kocsis,et al.  Transplantation of an acutely isolated bone marrow fraction repairs demyelinated adult rat spinal cord axons , 2001, Glia.

[23]  M. Wegner.  Expression of transcription factors during oligodendroglial development , 2001, Microscopy research and technique.

[24]  P. Morell,et al.  The Neurotoxicant, Cuprizone, as a Model to Study Demyelination and Remyelination in the Central Nervous System , 2001, Brain pathology.

[25]  Y. Qi,et al.  Selective Expression of Nkx-2.2 Transcription Factor in Chicken Oligodendrocyte Progenitors and Implications for the Embryonic Origin of Oligodendrocytes , 2000, Molecular and Cellular Neuroscience.

[26]  M. Nakafuku,et al.  Dynamic expression of basic helix-loop-helix Olig family members: implication of Olig2 in neuron and oligodendrocyte differentiation and identification of a new member, Olig3 , 2000, Mechanisms of Development.

[27]  M Chopp,et al.  Spinal cord injury in rat: treatment with bone marrow stromal cell transplantation , 2000, Neuroreport.

[28]  T. Holekamp,et al.  Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[29]  David J Anderson,et al.  Identification of a Novel Family of Oligodendrocyte Lineage-Specific Basic Helix–Loop–Helix Transcription Factors , 2000, Neuron.

[30]  Joanne Chan,et al.  Sonic Hedgehog–Regulated Oligodendrocyte Lineage Genes Encoding bHLH Proteins in the Mammalian Central Nervous System , 2000, Neuron.

[31]  W. Richardson,et al.  Oligodendrocyte lineage and the motor neuron connection , 2000, Glia.

[32]  J. Mcdonald,et al.  Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord , 1999, Nature Medicine.

[33]  T. Ben-Hur,et al.  From Neural Stem Cells to Myelinating Oligodendrocytes , 1999, Molecular and Cellular Neuroscience.

[34]  R. McKay,et al.  Embryonic stem cell-derived glial precursors: a source of myelinating transplants. , 1999, Science.

[35]  K. Suzuki,et al.  Microglial/macrophage accumulation during cuprizone-induced demyelination in C57BL/6 mice , 1998, Journal of Neuroimmunology.

[36]  P. Travers,et al.  Encephalitogenic epitopes of myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein for experimental allergic encephalomyelitis induction in Biozzi ABH (H-2Ag7) mice share an amino acid motif. , 1996, Journal of immunology.

[37]  Guy McKhann,et al.  Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain , 2004, Nature Medicine.