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  • Review Article
  • Published:

Remyelination in the CNS: from biology to therapy

Nature Reviews Neuroscience volume 9, pages 839–855 (2008)Cite this article

Key Points

  • CNS remyelination is the regenerative process by which myelin sheaths are restored to demyelinated axons. Unlike the poor regeneration that occurs following neuronal injury, remyelination can occur as a spontaneous and efficient process in experimental models and many clinical conditions.

  • Although remyelination can occur in multiple sclerosis (MS; a widely occurring demyelinating disease), it often fails, leaving axons demyelinated and vulnerable to degeneration. Recent studies have revealed the importance of the myelin sheath for maintaining axonal integrity and hence the importance of promoting remyelination in diseases such as MS as an effective means of neuroprotection.

  • Remyelination is mediated by a population of adult neural stem cells that are widely distributed throughout the CNS and that are commonly referred to as oligodendrocyte precursor cells (OPCs). These cells respond to demyelination by activation, proliferation, migration and finally differentiation into remyelinating oligodendrocytes; it is the last of these processes that is most likely to fail in MS and leave areas of demyelination containing oligodendrocyte-lineage cells that are unable to fully differentiate.

  • Remyelination is governed by a complex interaction of environmental signals and cell-intrinsic mechanisms that are triggered by the inflammatory response to injury. This response therefore has a key role in initiating remyelination. The network of signals that is involved in remyelination shows high levels of redundancy.

  • In theory, remyelination can be enhanced either by promoting endogenous remyelination or by transplanting myelinating cells. The first approach, which may have a pharmacological basis, is especially attractive for diseases such as MS in which remyelination occurs and will involve either the antagonism of negative regulatory pathways and/or the enhancement of positive regulatory pathways.

  • Cell therapy (transplantation) approaches to remyelination are expected to be of particular benefit for genetic demyelinating diseases in which there is an inherent defect in the oligodendrocyte lineage. Recent studies have provided proof-of-principle that human cells can be used to remyelinate the entire CNS in laboratory animal models.

Abstract

Remyelination involves reinvesting demyelinated axons with new myelin sheaths. In stark contrast to the situation that follows loss of neurons or axonal damage, remyelination in the CNS can be a highly effective regenerative process. It is mediated by a population of precursor cells called oligodendrocyte precursor cells (OPCs), which are widely distributed throughout the adult CNS. However, despite its efficiency in experimental models and in some clinical diseases, remyelination is often inadequate in demyelinating diseases such as multiple sclerosis (MS), the most common demyelinating disease and a cause of neurological disability in young adults. The failure of remyelination has profound consequences for the health of axons, the progressive and irreversible loss of which accounts for the progressive nature of these diseases. The mechanisms of remyelination therefore provide critical clues for regeneration biologists that help them to determine why remyelination fails in MS and in other demyelinating diseases and how it might be enhanced therapeutically.

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Figure 1: The fate of demyelinated axons.
Figure 2: MS — an inflammatory demyelinating disease with variable degrees of remyelination.
Figure 3: The phases of remyelination.
Figure 4: Epigenetic regulation of OPC differentiation during remyelination.
Figure 5: A schematic representation of the dysregulation hypothesis of remyelination failure.
Figure 6: Transplantation of human OPCs leads to widespread myelination of the brain in a mouse model of leukodystrophy.

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References

  1. Felts, P. A., Baker, T. A. & Smith, K. J. Conduction in segmentally demyelinated mammalian central axons. J. Neurosci. 17, 7267–7277 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Miller, R. H. & Bai, L. Cellular approaches for stimulating CNS remyelination. Regen. Med. 2, 817–829 (2007).

    CAS  PubMed  Google Scholar 

  3. Gallo, V. & Armstrong, R. C. Myelin repair strategies: a cellular view. Curr. Opin. Neurol. 21, 278–283 (2008).

    PubMed  PubMed Central  Google Scholar 

  4. Zawadzka, M. & Franklin, R. J. M. Myelin regeneration in demyelinating disorders: new developments in biology and clinical pathology. Curr. Opin. Neurol. 20, 294–298 (2007).

    PubMed  Google Scholar 

  5. Smith, K. J., Blakemore, W. F. & McDonald, W. I. Central remyelination restores secure conduction. Nature 280, 395–396 (1979). This important paper was the first to demonstrate functional recovery associated with remyelination following demyelination of CNS axons.

    CAS  PubMed  Google Scholar 

  6. Jeffery, N. D. & Blakemore, W. F. Locomotor deficits induced by experimental spinal cord demyelination are abolished by spontaneous remyelination. Brain 120, 27–37 (1997).

    PubMed  Google Scholar 

  7. Liebetanz, D. & Merkler, D. Effects of commissural de- and remyelination on motor skill behaviour in the cuprizone mouse model of multiple sclerosis. Exp. Neurol. 202, 217–224 (2006).

    CAS  PubMed  Google Scholar 

  8. Blakemore, W. F. Pattern of remyelination in the CNS. Nature 249, 577–578 (1974).

    CAS  PubMed  Google Scholar 

  9. Ludwin, S. K. & Maitland, M. Long-term remyelination fails to reconstitute normal thickness of central myelin sheaths. J. Neurol. Sci. 64, 193–198 (1984).

    CAS  PubMed  Google Scholar 

  10. Stidworthy, M. F., Genoud, S., Suter, U., Mantei, N. & Franklin, R. J. M. Quantifying the early stages of remyelination following cuprizone-induced demyelination. Brain Pathol. 13, 329–339 (2003).

    PubMed  Google Scholar 

  11. Michailov, G. V. et al. Axonal neuregulin-1 regulates myelin sheath thickness. Science 304, 700–703 (2004).

    CAS  PubMed  Google Scholar 

  12. Taveggia, C. et al. Type III neuregulin-1 promotes oligodendrocyte myelination. Glia 56, 284–293 (2008).

    PubMed  Google Scholar 

  13. Brinkmann, B. G. et al. Neuregulin-1/ErbB signaling serves distinct functions in myelination of the peripheral and central nervous system. Neuron 59, 581–594 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Franklin, R. J. M. & Hinks, G. L. Understanding CNS remyelination - clues from developmental and regeneration biology. J. Neurosci. Res. 58, 207–213 (1999).

    CAS  PubMed  Google Scholar 

  15. Mason, J. L., Langaman, C., Morell, P., Suzuki, K. & Matsushima, G. K. Episodic demyelination and subsequent remyelination within the murine central nervous system: changes in axonal calibre. Neuropathol. Appl. Neurobiol. 27, 50–58 (2001).

    CAS  PubMed  Google Scholar 

  16. Ingber, D. E. Cellular mechanotransduction: putting all the pieces together again. FASEB J. 20, 811–827 (2006).

    CAS  PubMed  Google Scholar 

  17. Blakemore, W. F. & Franklin, R. J. M. Remyelination in experimental models of toxin-induced demyelination. Curr. Top. Microbiol. Immunol. 318, 193–212 (2008).

    CAS  PubMed  Google Scholar 

  18. Blakemore, W. F. Remyelination of the superior cerebellar peduncle in the mouse following demyelination induced by feeding cuprizone. J. Neurol. Sci. 20, 73–83 (1973).

    CAS  PubMed  Google Scholar 

  19. Matsushima, G. K. & Morell, P. The neurotoxicant, cuprizone, as a model to study demyelination and remyelination in the central nervous system. Brain Pathol. 11, 107–116 (2001).

    CAS  PubMed  Google Scholar 

  20. Woodruff, R. H. & Franklin, R. J. M. Demyelination and remyelination of the caudal cerebellar peduncle of adult rats following stereotaxic injections of lysolecithin, ethidium bromide and complement/anti-galactocerebroside - a comparative study. Glia 25, 216–228 (1999).

    CAS  PubMed  Google Scholar 

  21. Shields, S. A., Gilson, J. M., Blakemore, W. F. & Franklin, R. J. M. Remyelination occurs as extensively but more slowly in old rats compared to young rats following gliotoxin-induced CNS demyelination. Glia 28, 77–83 (1999).

    CAS  PubMed  Google Scholar 

  22. Smith, P. M. & Jeffery, N. D. Histological and ultrastructural analysis of white matter damage after naturally-occurring spinal cord injury. Brain Pathol. 16, 99–109 (2006).

    PubMed  PubMed Central  Google Scholar 

  23. Lasiene, J., Shupe, L., Perlmutter, S. & Horner, P. No evidence for chronic demyelination in spared axons after spinal cord injury in a mouse. J. Neurosci. 28, 3887–3896 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Patrikios, P. et al. Remyelination is extensive in a subset of multiple sclerosis patients. Brain 129, 3165–3172 (2006). This study used post-mortem tissue to describe the extent of remyelination occurring in MS patients, revealing that although in some patients remyelination is a rare event, in others it can be much more extensive than previously thought (a similar conclusion is drawn in reference 25).

    PubMed  Google Scholar 

  25. Patani, R., Balaratnam, M., Vora, A. & Reynolds, R. Remyelination can be extensive in multiple sclerosis despite a long disease course. Neuropathol. Appl. Neurobiol. 33, 277–287 (2007).

    CAS  PubMed  Google Scholar 

  26. Linington, C., Engelhardt, B., Kapocs, G. & Lassman, H. Induction of persistently demyelinated lesions in the rat following the repeated adoptive transfer of encephalitogenic T cells and demyelinating antibody. J. Neuroimmunol. 40, 219–224 (1992).

    CAS  PubMed  Google Scholar 

  27. Merkler, D., Ernsting, T., Kerschensteiner, M., Bruck, W. & Stadelmann, C. A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination. Brain 129, 1972–1983 (2006).

    PubMed  Google Scholar 

  28. Skripuletz, T. et al. Cortical demyelination is prominent in the murine cuprizone model and is strain-dependent. Am. J. Pathol. 172, 1053–1061 (2008).

    PubMed  PubMed Central  Google Scholar 

  29. Albert, M., Antel, J., Bruck, W. & Stadelmann, C. Extensive cortical remyelination in patients with chronic multiple sclerosis. Brain Pathol. 17, 129–138 (2007).

    PubMed  PubMed Central  Google Scholar 

  30. Trapp, B. D. & Nave, K. A. Multiple sclerosis: an immune or neurodegenerative disorder? Annu. Rev. Neurosci. 31, 247–269 (2008).

    CAS  PubMed  Google Scholar 

  31. Irvine, K. A. & Blakemore, W. F. Remyelination protects axons from demyelination-associated axon degeneration. Brain 131, 1464–1477 (2008). This study used cell transplantation to provide experimental evidence that remyelination is protective to axons.

    CAS  PubMed  Google Scholar 

  32. Young, E. A. et al. Imaging correlates of decreased axonal Na+/K+ ATPase in chronic multiple sclerosis lesions. Ann. Neurol. 63, 428–435 (2008).

    PubMed  Google Scholar 

  33. Lappe-Siefke, C. et al. Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nature Genet. 33, 366–374 (2003).

    CAS  PubMed  Google Scholar 

  34. Griffiths, I. et al. Axonal swellings and degeneration in mice lacking the major proteolipid of myelin. Science 280, 1610–1613 (1998). This landmark paper was the first in a series of studies in which knockouts of oligodendrocyte-expressed genes were used to demonstrate the important role of the oligodendrocyte in maintaining axon integrity.

    CAS  PubMed  Google Scholar 

  35. Edgar, J. M. et al. Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia. J. Cell Biol. 166, 121–131 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Werner, H. B. et al. Proteolipid protein is required for transport of sirtuin 2 into CNS myelin. J. Neurosci. 27, 7717–7730 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Garbern, J. Y. et al. Patients lacking the major CNS myelin protein, proteolipid protein 1, develop length-dependent axonal degeneration in the absence of demyelination and inflammation. Brain 125, 551–561 (2002).

    PubMed  Google Scholar 

  38. Kornek, B. et al. Multiple sclerosis and chronic autoimmune encephalomyelitis: a comparative quantitative study of axonal injury in active, inactive, and remyelinated lesions. Am. J. Pathol. 157, 267–276 (2000). This study provided data suggesting that remyelination is associated with axon preservation in MS (see also reference31).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Wilkins, A., Majed, H., Layfield, R., Compston, A. & Chandran, S. Oligodendrocytes promote neuronal survival and axonal length by distinct intracellular mechanisms: a novel role for oligodendrocyte-derived glial cell line-derived neurotrophic factor. J. Neurosci. 23, 4967–4974 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Smith, K. J. Sodium channels and multiple sclerosis: roles in symptom production, damage and therapy. Brain Pathol. 17, 230–242 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Stys, P. K., Waxman, S. G. & Ransom, B. R. Ionic mechanisms of anoxic injury in mammalian CNS white matter: role of Na+ channels and Na+-Ca2+ exchanger. J. Neurosci. 12, 430–439 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Dutta, R. et al. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann. Neurol. 59, 478–489 (2006).

    CAS  PubMed  Google Scholar 

  43. Poliak, S. & Peles, E. The local differentiation of myelinated axons at nodes of Ranvier. Nature Rev. Neurosci. 4, 968–980 (2003).

    CAS  Google Scholar 

  44. Sherman, D. L. & Brophy, P. J. Mechanisms of axon ensheathment and myelin growth. Nature Rev. Neurosci. 6, 683–690 (2005).

    CAS  Google Scholar 

  45. Craner, M. J., Lo, A. C., Black, J. A. & Waxman, S. G. Abnormal sodium channel distribution in optic nerve axons in a model of inflammatory demyelination. Brain 126, 1552–1561 (2003).

    PubMed  Google Scholar 

  46. Waxman, S. G. Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Nature Rev. Neurosci. 7, 932–941 (2006).

    CAS  Google Scholar 

  47. Craner, M. J. et al. Molecular changes in neurons in multiple sclerosis: altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger. Proc. Natl Acad. Sci. USA 101, 8168–8173 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Prayoonwiwat, N. & Rodriguez, M. The potential for oligodendrocyte proliferation during demyelinating disease. J. Neuropathol. Exp. Neurol. 52, 55–63 (1993).

    CAS  PubMed  Google Scholar 

  49. Sim, F. J., Zhao, C., Penderis, J. & Franklin, R. J. M. The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and differentiation. J. Neurosci. 22, 2451–2459 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. ffrench-Constant, C. & Raff, M. C. Proliferating bipotential glial progenitor cells in adult rat optic nerve. Nature 319, 499–502 (1986). This was the first paper to describe adult OPCs, the cells responsible for CNS remyelination.

    CAS  PubMed  Google Scholar 

  51. Dawson, M. R. L., Polito, A., Levine, J. M. & Reynolds, R. NG2-expressing glial progenitor cells: an abundant and widespread population of cycling cells in the adult rat CNS. Mol. Cell. Neurosci. 24, 476–488 (2003).

    CAS  PubMed  Google Scholar 

  52. Sim, F. J. et al. Complementary patterns of gene expression by human oligodendrocyte progenitors and their environment predict determinants of progenitor maintenance and differentiation. Ann. Neurol. 59, 763–779 (2006).

    CAS  PubMed  Google Scholar 

  53. Levine, J. M., Reynolds, R. & Fawcett, J. W. The oligodendrocyte precursor cell in health and disease. Trends Neurosci. 24, 39–47 (2001).

    CAS  PubMed  Google Scholar 

  54. Horner, P. J. et al. Proliferation and differentiation of progenitor cells throughout the intact adult rat spinal cord. J. Neurosci. 20, 2218–2228 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Redwine, J. M. & Armstrong, R. C. In vivo proliferation of oligodendrocyte progenitors expressing PDGFαR during early remyelination. J. Neurobiol. 37, 413–428 (1998).

    CAS  PubMed  Google Scholar 

  56. Keirstead, H. S., Levine, J. M. & Blakemore, W. F. Response of the oligodendrocyte progenitor cell population (defined by NG2 labelling) to demyelination of the adult spinal cord. Glia 22, 161–170 (1998).

    CAS  PubMed  Google Scholar 

  57. Cenci di Bello, I., Dawson, M. R. L., Levine, J. M. & Reynolds, R. Generation of oligodendroglial progenitors in acute inflammatory demyelinating lesions of the rat brain stem is stimulated by demyelination rather than inflammation. J. Neurocytol. 28, 365–381 (1999).

    Google Scholar 

  58. Arnett, H. A. et al. The bHLH transcription factor Olig1 is required for repair of demyelinated lesions in the CNS. Science 306, 2111–2115 (2004). This paper described a critical role for the oligodendrocyte-lineage-specific basic helix–loop–helix transcription factor OLIG1 in remyelination, and specifically in the differentiation process by which adult OPCs become remyelinating oligodendrocytes.

    CAS  PubMed  Google Scholar 

  59. Kitada, M. & Rowitch, D. H. Transcription factor co-expression patterns indicate heterogeneity of oligodendroglial subpopulations in adult spinal cord. Glia 54, 35–46 (2006).

    PubMed  Google Scholar 

  60. Aguirre, A., Dupree, J. L., Mangin, J. M. & Gallo, V. A functional role for EGFR signalling in myelination and remyelination. Nature Neurosci. 10, 990–1002 (2007).

    CAS  PubMed  Google Scholar 

  61. Armstrong, R. C., Kim, J. G. & Hudson, L. D. Expression of myelin transcription factor I (MyTI), a “zinc- finger” DNA-binding protein, in developing oligodendrocytes. Glia 14, 303–321 (1995).

    CAS  PubMed  Google Scholar 

  62. Reynolds, R. & Hardy, R. Oligodendroglial progenitors labeled with the O4 antibody persist in the adult rat cerebral cortex in vivo. J. Neurosci. Res. 47, 455–470 (1997).

    CAS  PubMed  Google Scholar 

  63. Wren, D., Wolswijk, G. & Noble, M. In vitro analysis of the origin and maintenance of O-2Aadult progenitor cells. J. Cell Biol. 116, 167–176 (1992).

    CAS  PubMed  Google Scholar 

  64. Wolswijk, G. & Noble, M. Identification of an adult-specific glial progenitor cell. Development 105, 387–400 (1989).

    CAS  PubMed  Google Scholar 

  65. Wolswijk, G. & Noble, M. Cooperation between PDGF and FGF converts slowly dividing O-2Aadult progenitors to rapidly dividing cells with characteristics of O-2Aperinatal progenitor cells. J. Cell Biol. 118, 889–900 (1992). This paper revealed how adult OPCs can change their properties, in response to environmental factors (growth factors) that are upregulated following CNS demyelination, in a manner conducive to their role in remyelination.

    CAS  PubMed  Google Scholar 

  66. Hinks, G. L. & Franklin, R. J. M. Distinctive patterns of PDGF-A, FGF-2, IGF-I and TGF-β1 gene expression during remyelination of experimentally-induced spinal cord demyelination. Mol. Cell. Neurosci. 14, 153–168 (1999).

    CAS  PubMed  Google Scholar 

  67. Messersmith, D. J., Murtie, J. C., Le, T. Q., Frost, E. E. & Armstrong, R. C. Fibroblast growth factor 2 (FGF2) and FGF receptor expression in an experimental demyelinating disease with extensive remyelination. J. Neurosci. Res. 62, 241–256 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Gensert, J. M. & Goldman, J. E. Endogenous progenitors remyelinate demyelinated axons in the adult CNS. Neuron 19, 197–203 (1997).

    CAS  PubMed  Google Scholar 

  69. Carroll, W. M., Jennings, A. R. & Ironside, L. J. Identification of the adult resting progenitor cell by autoradiographic tracking of oligodendrocyte precursors in experimental CNS demyelination. Brain 121, 293–302 (1998).

    PubMed  Google Scholar 

  70. Groves, A. K. et al. Repair of demyelinated lesions by transplantation of purified O-2A progenitor cells. Nature 362, 453–455 (1993).

    CAS  PubMed  Google Scholar 

  71. Warrington, A. E., Barbarese, E. & Pfeiffer, S. E. Differential myelinogenic capacity of specific developmental stages of the oligodendrocyte lineage upon transplantation into hypomyelinating hosts. J. Neurosci. Res. 34, 1–13 (1993).

    CAS  PubMed  Google Scholar 

  72. Zhang, S. C., Ge, B. & Duncan, I. D. Adult brain retains the potential to generate oligodendroglial progenitors with extensive myelination capacity. Proc. Natl Acad. Sci. USA 96, 4089–4094 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Nunes, M. C. et al. Identification and isolation of multipotential neural progenitor cells from the subcortical white matter of the adult human brain. Nature Med. 9, 439–447 (2003). This paper described a study in which in vitro and transplantation approaches were used to demonstrate the multipotentiality of adult human OPCs (which can differentiate into both oligodendrocytes and neurons).

    CAS  PubMed  Google Scholar 

  74. Levine, J. M. & Reynolds, R. Activation and proliferation of endogenous oligodendrocyte precursor cells during ethidium bromide-induced demyelination. Exp. Neurol. 160, 333–347 (1999).

    CAS  PubMed  Google Scholar 

  75. Watanabe, M., Toyama, Y. & Nishiyama, A. Differentiation of proliferated NG2-positive glial progenitor cells in a remyelinating lesion. J. Neurosci. Res. 69, 826–836 (2002).

    CAS  PubMed  Google Scholar 

  76. Fancy, S. P. J., Zhao, C. & Franklin, R. J. M. Increased expression of Nkx2.2 and Olig2 identifies reactive oligodendrocyte progenitor cells responding to demyelination in the adult CNS. Mol. Cell. Neurosci. 27, 247–254 (2004).

    CAS  PubMed  Google Scholar 

  77. Nait-Oumesmar, B. et al. Progenitor cells of the adult mouse subventricular zone proliferate, migrate and differentiate into oligodendrocytes after demyelination. Eur. J. Neurosci. 11, 4357–4366 (1999).

    CAS  PubMed  Google Scholar 

  78. Picard-Riera, N. et al. Experimental autoimmune encephalomyelitis mobilizes neural progenitors from the subventricular zone to undergo oligodendrogenesis in adult mice. Proc. Natl Acad. Sci USA 99, 13211–13216 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Menn, B. et al. Origin of oligodendrocytes in the subventricular zone of the adult brain. J. Neurosci. 26, 7907–7918 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Magalon, K., Cantarella, C., Monti, G., Cayre, M. & Durbec, P. Enriched environment promotes adult neural progenitor cell mobilization in mouse demyelination models. Eur. J. Neurosci. 25, 761–771 (2007).

    PubMed  Google Scholar 

  81. Cantarella, C., Cayre, M., Magalon, K. & Durbec, P. Intranasal HB-EGF administration favors adult SVZ cell mobilization to demyelinated lesions in mouse corpus callosum. Dev. Neurobiol. 68, 223–236 (2008).

    PubMed  Google Scholar 

  82. Nait-Oumesmar, B. et al. Activation of the subventricular zone in multiple sclerosis: evidence for early glial progenitors. Proc. Natl Acad. Sci. USA 104, 4694–4699 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Lucchinetti, C. et al. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann. Neurol. 47, 707–717 (2000).

    CAS  PubMed  Google Scholar 

  84. Keirstead, H. S. & Blakemore, W. F. Identification of post-mitotic oligodendrocytes incapable of remyelination within the demyelinated adult spinal cord. J. Neuropathol. Exp. Neurol. 56, 1191–1201 (1997).

    CAS  PubMed  Google Scholar 

  85. Targett, M. P. et al. Failure to remyelinate rat axons following transplantation of glial cells obtained from adult human brain. Neuropathol. Appl. Neurobiol. 22, 199–206 (1996).

    CAS  PubMed  Google Scholar 

  86. Bergles, D. E., Roberts, J. D., Somogyi, P. & Jahr, C. E. Glutamatergic synapses on oligodendrocyte precursor cells in the hippocampus. Nature 405, 187–191 (2000).

    CAS  PubMed  Google Scholar 

  87. Jabs, R. et al. Synaptic transmission onto hippocampal glial cells with hGFAP promoter activity. J. Cell Sci. 118, 3791–3803 (2005).

    CAS  PubMed  Google Scholar 

  88. Karadottir, R., Cavelier, P., Bergersen, L. H. & Attwell, D. NMDA receptors are expressed in oligodendrocytes and activated in ischaemia. Nature 438, 1162–1166 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Ziskin, J. L., Nishiyama, A., Rubio, M., Fukaya, M. & Bergles, D. E. Vesicular release of glutamate from unmyelinated axons in white matter. Nature Neurosci. 10, 321–330 (2007).

    CAS  PubMed  Google Scholar 

  90. Kukley, M., Capetillo-Zarate, E. & Dietrich, D. Vesicular glutamate release from axons in white matter. Nature Neurosci. 10, 311–320 (2007).

    CAS  PubMed  Google Scholar 

  91. Karadottir, R., Hamilton, N. B., Bakiri, Y. & Attwell, D. Spiking and nonspiking classes of oligodendrocyte precursor glia in CNS white matter. Nature Neurosci. 11, 450–456 (2008).

    CAS  PubMed  Google Scholar 

  92. Mason, J. L. & Goldman, J. E. A2B5+ and O4+ cycling progenitors in the adult forebrain white matter respond differentially to PDGF-AA, FGF-2, and IGF-1. Mol. Cell. Neurosci. 20, 30–42 (2002).

    CAS  PubMed  Google Scholar 

  93. Richardson, W. D., Kessaris, N. & Pringle, N. Oligodendrocyte wars. Nature Rev. Neurosci. 7, 11–18 (2006).

    CAS  Google Scholar 

  94. Kessaris, N. et al. Competing waves of oligodendrocytes in the forebrain and postnatal elimination of an embryonic lineage. Nature Neurosci. 9, 173–179 (2006).

    CAS  PubMed  Google Scholar 

  95. Cai, J. et al. Generation of oligodendrocyte precursor cells from mouse dorsal spinal cord independent of nkx6 regulation and shh signaling. Neuron 45, 41–53 (2005).

    CAS  PubMed  Google Scholar 

  96. Reynolds, R. et al. The response of NG2-expressing oligodendrocyte progenitors to demyelination in MOG-EAE and MS. J. Neurocytol. 31, 523–536 (2002).

    PubMed  Google Scholar 

  97. Watanabe, M., Hadzic, T. & Nishiyama, A. Transient upregulation of Nkx2.2 expression in oligodendrocyte lineage cells during remyelination. Glia 46, 311–322 (2004).

    PubMed  Google Scholar 

  98. Talbott, J. F. et al. Endogenous Nkx2.2+/Olig2+ oligodendrocyte precursor cells fail to remyelinate the demyelinated adult rat spinal cord in the absence of astrocytes. Exp. Neurol. 192, 11–24 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Vana, A. C., Lucchinetti, C. F., Le, T. Q. & Armstrong, R. C. Myelin transcription factor 1 (Myt1) expression in demyelinated lesions of rodent and human CNS. Glia 55, 687–697 (2007).

    PubMed  PubMed Central  Google Scholar 

  100. Shen, S. et al. Age-dependent epigenetic control of differentiation inhibitors: a critical determinant of remyelination efficiency. Nature Neurosci. 11, 1024–1034 (2008). Several earlier studies showed that, like other regenerative processes, the efficiency of remyelination declines with age. This paper provided mechanistic insights into how OPC differentiation is regulated during remyelination and how these mechanisms change with aging.

    CAS  PubMed  Google Scholar 

  101. Glezer, I., Lapointe, A. & Rivest, S. Innate immunity triggers oligodendrocyte progenitor reactivity and confines damages to brain injuries. FASEB J. 20, 750–752 (2006).

    CAS  PubMed  Google Scholar 

  102. Rhodes, K. E., Raivich, G. & Fawcett, J. W. The injury response of oligodendrocyte precursor cells is induced by platelets, macrophages and inflammation-associated cytokines. Neuroscience 140, 87–100 (2006).

    CAS  PubMed  Google Scholar 

  103. Nielsen, H. H., Ladeby, R., Drojdahl, N., Peterson, A. C. & Finsen, B. Axonal degeneration stimulates the formation of NG2+ cells and oligodendrocytes in the mouse. Glia 54, 105–115 (2006).

    PubMed  Google Scholar 

  104. Schonrock, L. M., Kuhlmann, T., Adler, S., Bitsch, A. & Bruck, W. Identification of glial cell proliferation in early multiple sclerosis lesions. Neuropathol. Appl. Neurobiol. 24, 320–330 (1998).

    CAS  PubMed  Google Scholar 

  105. Prineas, J. W. et al. Multiple sclerosis: oligodendrocyte proliferation and differentiation in fresh lesions. Lab. Invest. 61, 489–503 (1989).

    CAS  PubMed  Google Scholar 

  106. Wilson, H. C., Scolding, N. J. & Raine, C. S. Co-expression of PDGFα receptor and NG2 by oligodendrocyte precursors in human CNS and multiple sclerosis lesions. J. Neuroimmunol. 176, 162–173 (2006).

    CAS  PubMed  Google Scholar 

  107. Scolding, N. et al. Oligodendrocyte progenitors are present in the normal adult human CNS and in the lesions of multiple sclerosis. Brain 121, 2221–2228 (1998).

    PubMed  Google Scholar 

  108. Carroll, W. M. & Jennings, A. R. Early recruitment of oligodendrocyte precursors in CNS remyelination. Brain 117, 563–578 (1994).

    PubMed  Google Scholar 

  109. Crockett, D. P., Burshteyn, M., Garcia, C., Muggironi, M. & Casaccia-Bonnefil, P. Number of oligodendrocyte progenitors recruited to the lesioned spinal cord is modulated by the levels of the cell cycle regulatory protein p27Kip-1. Glia 49, 301–308 (2005).

    PubMed  Google Scholar 

  110. Woodruff, R. H., Fruttiger, M., Richardson, W. D. & Franklin, R. J. M. Platelet-derived growth factor regulates oligodendrocyte progenitor numbers in adult CNS and their response following CNS demyelination. Mol. Cell. Neurosci. 25, 252–262 (2004).

    CAS  PubMed  Google Scholar 

  111. Murtie, J. C., Zhou, Y. X., Le, T. Q., Vana, A. C. & Armstrong, R. C. PDGF and FGF2 pathways regulate distinct oligodendrocyte lineage responses in experimental demyelination with spontaneous remyelination. Neurobiol. Dis. 19, 171–182 (2005).

    CAS  PubMed  Google Scholar 

  112. Zhou, Y. X., Flint, N. C., Murtie, J. C., Le, T. Q. & Armstrong, R. C. Retroviral lineage analysis of fibroblast growth factor receptor signaling in FGF2 inhibition of oligodendrocyte progenitor differentiation. Glia 54, 578–590 (2006).

    PubMed  PubMed Central  Google Scholar 

  113. Franklin, R. J. M. Why does remyelination fail in multiple sclerosis? Nature Rev. Neurosci. 3, 705–714 (2002).

    CAS  Google Scholar 

  114. Larsen, P. H., Wells, J. E., Stallcup, W. B., Opdenakker, G. & Yong, V. W. Matrix metalloproteinase-9 facilitates remyelination in part by processing the inhibitory NG2 proteoglycan. J. Neurosci. 23, 11127–11135 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Armstrong, R. C., Le, T. Q., Frost, E. E., Borke, R. C. & Vana, A. C. Absence of fibroblast growth factor 2 promotes oligodendroglial repopulation of demyelinated white matter. J. Neurosci. 22, 8574–8585 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Mason, J. L., Xuan, S., Dragatsis, I., Efstratiadis, A. & Goldman, J. E. Insulin-like growth factor (IGF) signaling through type 1 IGF receptor plays an important role in remyelination. J. Neurosci. 23, 7710–7718 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Xin, M. et al. Myelinogenesis and axonal recognition by oligodendrocytes in brain are uncoupled in Olig1-null mice. J. Neurosci. 25, 1354–1365 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Wang, S. et al. Notch receptor activation inhibits oligodendrocyte differentiation. Neuron 21, 63–75 (1998).

    PubMed  Google Scholar 

  119. Genoud, S. et al. Notch1 control of oligodendrocyte differentiation in the spinal cord. J. Cell Biol. 158, 709–718 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Zhou, Y. X. & Armstrong, R. C. Interaction of fibroblast growth factor 2 (FGF2) and notch signaling components in inhibition of oligodendrocyte progenitor (OP) differentiation. Neurosci. Lett. 421, 27–32 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Hu, Q. D. et al. F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation. Cell 115, 163–175 (2003).

    CAS  PubMed  Google Scholar 

  122. Stidworthy, M. F. et al. Notch1 and Jagged1 are expressed after CNS demyelination but are not a major rate-determining factor during remyelination. Brain 127, 1928–1941 (2004).

    PubMed  Google Scholar 

  123. Ludwin, S. K. Chronic demyelination inhibits remyelination in the central nervous system. Lab. Invest. 43, 382–387 (1980).

    CAS  PubMed  Google Scholar 

  124. Morell, P. et al. Gene expression in brain during cuprizone-induced demyelination and remyelination. Mol. Cell. Neurosci. 12, 220–227 (1998).

    CAS  PubMed  Google Scholar 

  125. Raine, C. S. & Wu, E. Multiple sclerosis: remyelination in acute lesions. J. Neuropathol. Exp. Neurol. 52, 199–204 (1993).

    CAS  PubMed  Google Scholar 

  126. Wolswijk, G. Oligodendrocyte precursor cells in the demyelinated multiple sclerosis spinal cord. Brain 125, 338–349 (2002).

    PubMed  Google Scholar 

  127. Kotter, M. R., Setzu, A., Sim, F. J., van Rooijen, N. & Franklin, R. J. M. Macrophage depletion impairs oligodendrocyte remyelination following lysolecithin-induced demyelination. Glia 35, 204–212 (2001).

    CAS  PubMed  Google Scholar 

  128. Kotter, M. R., Zhao, C., van Rooijen, N. & Franklin, R. J. M. Macrophage-depletion induced impairment of experimental CNS remyelination is associated with a reduced oligodendrocyte progenitor cell response and altered growth factor expression. Neurobiol. Dis. 18, 166–175 (2005).

    CAS  PubMed  Google Scholar 

  129. Li, W.-W., Setzu, A., Zhao, C. & Franklin, R. J. M. Minocycline-mediated inhibition of microglia activation impairs oligodendrocyte progenitor cell responses and remyelination in a non-immune model of demyelination. J. Neuroimmunol. 158, 58–66 (2005).

    CAS  PubMed  Google Scholar 

  130. Chari, D. M., Zhao, C., Kotter, M. R., Blakemore, W. F. & Franklin, R. J. M. Corticosteroids delay remyelination of experimental demyelination in the rodent central nervous system. J. Neurosci. Res. 83, 594–605 (2006).

    CAS  PubMed  Google Scholar 

  131. Bieber, A. J., Kerr, S. & Rodriguez, M. Efficient central nervous system remyelination requires T cells. Ann. Neurol. 53, 680–684 (2003).

    PubMed  Google Scholar 

  132. Biancotti, J. C., Kumar, S. & de Vellis, J. Activation of inflammatory response by a combination of growth factors in cuprizone-induced demyelinated brain leads to myelin repair. Neurochem. Res. 26 July 2008 (doi:10.1007/s11064-008-9792-8).

    CAS  PubMed  Google Scholar 

  133. Mason, J. L., Suzuki, K., Chaplin, D. D. & Matsushima, G. K. Interleukin-1β promotes repair of the CNS. J. Neurosci. 21, 7046–7052 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Arnett, H. A. et al. TNFα promotes proliferation of oligodendrocyte progenitors and remyelination. Nature Neurosci. 4, 1116–1122 (2001).

    CAS  PubMed  Google Scholar 

  135. Plant, S. R. et al. Lymphotoxin β receptor (LtβR): dual roles in demyelination and remyelination and successful therapeutic intervention using LtβR-Ig protein. J. Neurosci. 27, 7429–7437 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Arnett, H. A., Wang, Y., Matsushima, G. K., Suzuki, K. & Ting, J. P. Functional genomic analysis of remyelination reveals importance of inflammation in oligodendrocyte regeneration. J. Neurosci. 23, 9824–9832 (2003). This study used a genomic-transcription profiling approach combined with a toxin model of demyelination–remyelination (the cuprizone model) to identify the key role that the inflammatory response to demyelination has in facilitating remyelination.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Lin, W. et al. Interferon-γ inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress. Brain 129, 1306–1318 (2006).

    PubMed  Google Scholar 

  138. Robinson, S. & Miller, R. H. Contact with central nervous system myelin inhibits oligodendrocyte progenitor maturation. Dev. Biol. 216, 359–368 (1999).

    CAS  PubMed  Google Scholar 

  139. Kotter, M. R., Li, W.-W., Zhao, C. & Franklin, R. J. M. Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J. Neurosci. 26, 328–332 (2006). It is well established that CNS myelin contains proteins that are inhibitory to axon regeneration. This study revealed that CNS myelin is also inhibitory to remyelination, preventing OPCs from differentiating into remyelinating oligodendrocytes. The role of phagocytic macrophages in removing myelin debris following demyelination is therefore critical to successful remyelination.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Syed, Y. A. et al. Inhibition of oligodendrocyte precursor cell differentiation by myelin-associated proteins. Neurosurg. Focus 24, E5 (2008).

    PubMed  Google Scholar 

  141. Setzu, A. et al. Inflammation stimulates myelination by transplanted oligodendrocyte precursor cells. Glia 54, 297–303 (2006).

    PubMed  Google Scholar 

  142. Li, W.-W., Penderis, J., Zhao, C., Schumacher, M. & Franklin, R. J. M. Females remyelinate more efficiently than males following demyelination in the aged but not young adult CNS. Exp. Neurol. 202, 250–254 (2006).

    CAS  PubMed  Google Scholar 

  143. Bieber, A. J., Ure, D. R. & Rodriguez, M. Genetically dominant spinal cord repair in a murine model of chronic progressive multiple sclerosis. J. Neuropathol. Exp. Neurol. 64, 46–57 (2005).

    CAS  PubMed  Google Scholar 

  144. Rando, T. A. Stem cells, ageing and the quest for immortality. Nature 441, 1080–1086 (2006).

    CAS  PubMed  Google Scholar 

  145. Irvine, K. A. & Blakemore, W. F. Age increases axon loss associated with primary demyelination in cuprizone-induced demyelination in C57BL/6 mice. J. Neuroimmunol. 175, 69–76 (2006).

    CAS  PubMed  Google Scholar 

  146. Wolswijk, G. Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J. Neurosci. 18, 601–609 (1998). This study was the first to draw attention to the presence of oligodendrocyte-lineage cells in areas of chronic demyelination in MS, pointing to the failure of differentiation as a major explanation for the failure of remyelination (see also references147–149).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Chang, A., Nishiyama, A., Peterson, J., Prineas, J. & Trapp, B. D. NG2-positive oligodendrocyte progenitor cells in adult human brain and multiple sclerosis lesions. J. Neurosci. 20, 6404–6412 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Chang, A., Tourtellotte, W. W., Rudick, R. & Trapp, B. D. Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. N. Engl. J. Med. 346, 165–173 (2002).

    PubMed  Google Scholar 

  149. Kuhlmann, T. et al. Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain 131, 1749–1758 (2008).

    CAS  PubMed  Google Scholar 

  150. Zhao, C., Li, W.-W. & Franklin, R. J. M. Differences in the early inflammatory responses to toxin-induced demyelination are associated with the age-related decline in CNS remyelination. Neurobiol. Aging 27, 1298–1307 (2006).

    CAS  PubMed  Google Scholar 

  151. Hinks, G. L. & Franklin, R. J. M. Delayed changes in growth factor gene expression during slow remyelination in the CNS of aged rats. Mol. Cell. Neurosci. 16, 542–556 (2000).

    CAS  PubMed  Google Scholar 

  152. Tang, D. G., Tokumoto, Y. M. & Raff, M. C. Long-term culture of purified postnatal oligodendrocyte precursor cells. Evidence for an intrinsic maturation program that plays out over months. J. Cell Biol. 148, 971–984 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Chari, D. M., Crang, A. J. & Blakemore, W. F. Decline in rate of colonization of oligodendrocyte progenitor cell (OPC)-depleted tissue by adult OPCs with age. J. Neuropathol. Exp. Neurol. 62, 908–916 (2003).

    CAS  PubMed  Google Scholar 

  154. Marin-Husstege, M., Muggironi, M., Liu, A. & Casaccia-Bonnefil, P. Histone deacetylase activity is necessary for oligodendrocyte lineage progression. J. Neurosci. 22, 10333–10345 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Shen, S., Li, J. & Casaccia-Bonnefil, P. Histone modifications affect timing of oligodendrocyte progenitor differentiation in the developing rat brain. J. Cell Biol. 169, 577–589 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Conboy, I. M. et al. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433, 760–764 (2005).

    CAS  PubMed  Google Scholar 

  157. Ibanez, C. et al. Systemic progesterone administration results in a partial reversal of the age-associated decline in CNS remyelination following toxin-induced demyelination in male rats. Neuropathol. Appl. Neurobiol. 30, 80–89 (2004).

    CAS  PubMed  Google Scholar 

  158. Chari, D. M. & Blakemore, W. F. Efficient recolonisation of progenitor-depleted areas of the CNS by adult oligodendrocyte progenitor cells. Glia 37, 307–313 (2002).

    PubMed  Google Scholar 

  159. Penderis, J., Shields, S. A. & Franklin, R. J. M. Impaired remyelination and depletion of oligodendrocyte progenitors does not occur following repeated episodes of focal demyelination in the rat CNS. Brain 126, 1382–1391 (2003). This paper described an experimental study demonstrating that repeat episodes of demyelination and remyelination at the same white matter region do not lead to OPC depletion or impaired remyelination.

    PubMed  Google Scholar 

  160. Mason, J. L. et al. Oligodendrocytes and progenitors become progressively depleted within chronically demyelinated lesions. Am. J. Pathol. 164, 1673–1682 (2004).

    PubMed  PubMed Central  Google Scholar 

  161. Armstrong, R. C., Le, T. Q., Flint, N. C., Vana, A. C. & Zhou, Y. X. Endogenous cell repair of chronic demyelination. J. Neuropathol. Exp. Neurol. 65, 245–256 (2006).

    PubMed  Google Scholar 

  162. Vana, A. C. et al. Platelet-derived growth factor promotes repair of chronically demyelinated white matter. J. Neuropathol. Exp. Neurol. 66, 975–988 (2007). Growth-factor-based strategies for enhancing remyelination have generally not been successful. For example, the OPC mitogen and chemoattractant PDGF does not increase remyelination following acute demyelination (see reference 110). However, this study used a model of chronic sustained demyelination to show how PDGF can be used to stimulate a more robust OPC response and hence improved remyelination.

    CAS  PubMed  Google Scholar 

  163. Niehaus, A. et al. Patients with active relapsing-remitting multiple sclerosis synthesize antibodies recognizing oligodendrocyte progenitor cell surface protein: implications for remyelination. Ann. Neurol. 48, 362–371 (2000). This paper provided evidence that OPCs might be a direct target of the disease process in MS patients. If this is the case, then these patients may have impaired remyelination owing to a paucity of OPCs. The relationship between these patients and those that have poor remyelination (see reference 24) remains to be established.

    CAS  PubMed  Google Scholar 

  164. Williams, A. et al. Semaphorin 3A and 3F: key players in myelin repair in multiple sclerosis? Brain 130, 2554–2565 (2007).

    PubMed  Google Scholar 

  165. John, G. R. et al. Multiple sclerosis: re-expression of a developmental pathway that restricts oligodendrocyte maturation. Nature Med. 8, 1115–1121 (2002).

    CAS  PubMed  Google Scholar 

  166. Seifert, T., Bauer, J., Weissert, R., Fazekas, F. & Storch, M. K. Notch1 and its ligand Jagged1 are present in remyelination in a T-cell- and antibody-mediated model of inflammatory demyelination. Acta Neuropathol. 113, 195–203 (2007).

    CAS  PubMed  Google Scholar 

  167. Jurynczyk, M., Jurewicz, A., Bielecki, B., Raine, C. S. & Selmaj, K. Inhibition of Notch signaling enhances tissue repair in an animal model of multiple sclerosis. J. Neuroimmunol. 170, 3–10 (2005).

    CAS  PubMed  Google Scholar 

  168. Tsai, H. H. et al. The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration. Cell 110, 373–383 (2002).

    CAS  PubMed  Google Scholar 

  169. Lindner, M. et al. The chemokine receptor CXCR2 is differentially regulated on glial cells in vivo but is not required for successful remyelination after cuprizone-induced demyelination. Glia 56, 1104–1113 (2008).

    PubMed  Google Scholar 

  170. Relvas, J. B. et al. Expression of dominant-negative and chimeric subunits reveals an essential role for β1 integrin during myelination. Curr. Biol. 11, 1039–1043 (2001).

    CAS  PubMed  Google Scholar 

  171. Benninger, Y. et al. β1-integrin signaling mediates premyelinating oligodendrocyte survival but is not required for CNS myelination and remyelination. J. Neurosci. 26, 7665–7673 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Selvaraju, R. et al. Osteopontin is upregulated during in vivo demyelination and remyelination and enhances myelin formation in vitro. Mol. Cell. Neurosci. 25, 707–721 (2004).

    CAS  PubMed  Google Scholar 

  173. Zhao, C., Fancy, S. P. J., ffrench-Constant, C. & Franklin, R. J. M. Osteopontin is extensively expressed by macrophages following CNS demyelination but has a redundant role in remyelination. Neurobiol. Dis. 31, 209–217 (2008).

    PubMed  Google Scholar 

  174. Back, S. A. et al. Hyaluronan accumulates in demyelinated lesions and inhibits oligodendrocyte progenitor maturation. Nature Med. 11, 966–972 (2005). This paper described a study that used in vitro techniques, animal models and MS-pathology approaches, and presents a compelling case that accumulation of the glycosaminoglycan hyaluronan is a powerful inhibitor of remyelination in MS.

    CAS  PubMed  Google Scholar 

  175. Charles, P. et al. Re-expression of PSA-NCAM by demyelinated axons: an inhibitor or remyelination in multiple sclerosis? Brain 125, 1972–1979 (2002).

    PubMed  Google Scholar 

  176. Charles, P. et al. Negative regulation of central nervous system myelination by polysialylated-neural cell adhesion molecule. Proc. Natl Acad. Sci. USA 97, 7585–7590 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Setzu, A., ffrench-Constant, C. & Franklin, R. J. M. CNS axons retain their competence for myelination throughout life. Glia 45, 307–311 (2004).

    PubMed  Google Scholar 

  178. Foote, A. K. & Blakemore, W. F. Inflammation stimulates remyelination in areas of chronic demyelination. Brain 128, 528–539 (2005).

    CAS  PubMed  Google Scholar 

  179. Franklin, R. J. M., Crang, A. J. & Blakemore, W. F. Transplanted type-1 astrocytes facilitate repair of demyelinating lesions by host oligodendrocytes in adult rat spinal cord. J. Neurocytol. 20, 420–430 (1991).

    CAS  PubMed  Google Scholar 

  180. Albrecht, P. J. et al. Astrocytes produce CNTF during the remyelination phase of viral-induced spinal cord demyelination to stimulate FGF-2 production. Neurobiol. Dis. 13, 89–101 (2003).

    CAS  PubMed  Google Scholar 

  181. Williams, A., Piaton, G. & Lubetzki, C. Astrocytes—friends or foes in multiple sclerosis? Glia 55, 1300–1312 (2007).

    PubMed  Google Scholar 

  182. Chesik, D., Wilczak, N. & De Keyser, J. The insulin-like growth factor system in multiple sclerosis. Int. Rev. Neurobiol. 79, 203–226 (2007).

    CAS  PubMed  Google Scholar 

  183. Baron, W., Colognato, H. & ffrench-Constant, C. Integrin-growth factor interactions as regulators of oligodendroglial development and function. Glia 49, 467–479 (2005).

    PubMed  Google Scholar 

  184. Gokhan, S. et al. Combinatorial profiles of oligodendrocyte-selective classes of transcriptional regulators differentially modulate myelin basic protein gene expression. J. Neurosci. 25, 8311–8321 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Shen, S., Liu, A., Li, J., Wolubah, C. & Casaccia-Bonnefil, P. Epigenetic memory loss in aging oligodendrocytes in the corpus callosum. Neurobiol. Aging 29, 452–463 (2008).

    CAS  PubMed  Google Scholar 

  186. Hemmer, B. & Hartung, H. P. Toward the development of rational therapies in multiple sclerosis: what is on the horizon? Ann. Neurol. 62, 314–326 (2007).

    CAS  PubMed  Google Scholar 

  187. Duncan, I. D., Aguayo, A. J., Bunge, R. P. & Wood, P. M. Transplantation of rat Schwann cells grown in tissue culture into the mouse spinal cord. J. Neurol. Sci. 49, 241–252 (1981).

    CAS  PubMed  Google Scholar 

  188. Lachapelle, F. et al. Transplantation of CNS fragments into brain of shiverer mutant mice: extensive myelination by implanted oligodendrocytes. I. Immunohistochemical studies. Dev. Neurosci. 6, 325–334 (1984). This landmark study used laboratory animals with genetic abnormalities in myelination as transplant recipients to test the myelination potential of transplanted cells.

    CAS  Google Scholar 

  189. Blakemore, W. F. & Crang, A. J. The use of cultured autologous Schwann cells to remyelinate areas of persistent demyelination in the central nervous system. J. Neurol. Sci. 70, 207–223 (1985).

    CAS  PubMed  Google Scholar 

  190. Windrem, M. S. et al. Fetal and adult human oligodendrocyte progenitor cell isolates myelinate the congenitally dysmyelinated brain. Nature Med. 10, 93–97 (2004).

    CAS  PubMed  Google Scholar 

  191. Honmou, O., Felts, P. A., Waxman, S. G. & Kocsis, J. D. Restoration of normal conduction properties in demyelinated spinal cord axons in the adult rat by transplantation of exogenous Schwann cells. J. Neurosci. 16, 3199–3208 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  192. Bachelin, C. et al. Efficient myelin repair in the macaque spinal cord by autologous grafts of Schwann cells. Brain 128, 540–549 (2005).

    PubMed  Google Scholar 

  193. Franklin, R. J. M., Gilson, J. M., Franceschini, I. A. & Barnett, S. C. Schwann cell-like myelination following transplantation of an olfactory bulb-ensheathing cell line into areas of demyelination in the adult CNS. Glia 17, 217–224 (1996).

    CAS  PubMed  Google Scholar 

  194. Imaizumi, T., Lankford, K. L., Waxman, S. G., Greer, C. A. & Kocsis, J. D. Transplanted olfactory ensheathing cells remyelinate and enhance axonal conduction in the demyelinated dorsal columns of the rat spinal cord. J. Neurosci. 18, 6176–6185 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Barnett, S. C. et al. Identification of a human olfactory ensheathing cell that can effect transplant-mediated remyelination of demyelinated CNS axons. Brain 123, 1581–1588 (2000).

    PubMed  Google Scholar 

  196. Hammang, J. P., Archer, D. R. & Duncan, I. D. Myelination following transplantation of EGF-responsive neural stem cells into a myelin-deficient environment. Exp. Neurol. 147, 84–95 (1997).

    CAS  PubMed  Google Scholar 

  197. Brustle, O. et al. Embryonic stem cell-derived glial precursors: a source of myelinating transplants. Science 285, 754–756 (1999). This was the first study to demonstrate the use of ES cells in transplant-mediated myelination.

    CAS  PubMed  Google Scholar 

  198. Archer, D. R., Cuddon, P. A., Lipsitz, D. & Duncan, I. D. Myelination of the canine central nervous system by glial cell transplantation: a model for repair of human myelin disease. Nature Med. 3, 54–59 (1997). This paper described the use of a large-animal model of demyelination (the shaking pup) as an important translational tool in developing cell-therapy approaches to remyelination.

    CAS  PubMed  Google Scholar 

  199. Windrem, M. S. et al. Neonatal chimerization with human glial progenitor cells can both remyelinate and rescue the otherwise lethally hypomyelinated shiverer mouse. Cell Stem Cell 2, 553–565 (2008). This paper provided dramatic proof-of-principle that the entire CNS can be populated by transplanted cells, and thus demonstrated that cell therapies for genetic demyelinating disease are a feasible proposition.

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Billiards, S. S. et al. Myelin abnormalities without oligodendrocyte loss in periventricular leukomalacia. Brain Pathol. 18, 153–163 (2008).

    PubMed  PubMed Central  Google Scholar 

  201. Pluchino, S. et al. Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 422, 688–694 (2003).

    CAS  PubMed  Google Scholar 

  202. Ben Hur, T. et al. Transplanted multipotential neural precursor cells migrate into the inflamed white matter in response to experimental autoimmune encephalomyelitis. Glia 41, 73–80 (2003).

    PubMed  Google Scholar 

  203. Pluchino, S. et al. Neurosphere-derived multipotent precursors promote neuroprotection by an immunomodulatory mechanism. Nature 436, 266–271 (2005).

    CAS  PubMed  Google Scholar 

  204. Einstein, O. et al. Neural precursors attenuate autoimmune encephalomyelitis by peripheral immunosuppression. Ann. Neurol. 61, 209–218 (2007).

    CAS  PubMed  Google Scholar 

  205. Kohama, I. et al. Transplantation of cryopreserved adult human Schwann cells enhances axonal conduction in demyelinated spinal cord. J. Neurosci. 21, 944–950 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Nistor, G. I., Totoiu, M. O., Haque, N., Carpenter, M. K. & Keirstead, H. S. Human embryonic stem cells differentiate into oligodendrocytes in high purity and myelinate after spinal cord transplantation. Glia 49, 385–396 (2005).

    PubMed  Google Scholar 

  207. Wang, Z., Colognato, H. & ffrench-Constant, C. Contrasting effects of mitogenic growth factors on myelination in neuron-oligodendrocyte co-cultures. Glia 55, 537–545 (2007).

    PubMed  Google Scholar 

  208. Pavelko, K. D., Van Engelen, B. G. M. & Rodriguez, M. Acceleration in the rate of CNS remyelination in lysolecithin-induced demyelination. J. Neurosci. 18, 2498–2505 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Bieber, A. J. et al. Human antibodies accelerate the rate of remyelination following lysolecithin-induced demyelination in mice. Glia 37, 241–249 (2002).

    PubMed  Google Scholar 

  210. Miller, D. J. & Rodriguez, M. Spontaneous and induced remyelination in multiple sclerosis and the Theiler's virus model of central nervous system demyelination. Microsc. Res. Tech. 32, 230–245 (1995).

    CAS  PubMed  Google Scholar 

  211. Njenga, M. K. et al. Absence of spontaneous central nervous system remyelination in class II-deficient mice infected with Theiler's virus. J. Neuropathol. Exp. Neurol. 58, 78–91 (1999).

    CAS  PubMed  Google Scholar 

  212. Liu, X. et al. Insulin-like growth factor-I treatment reduces immune cell responses in acute non-demyelinative experimental autoimmune encephalomyelitis. J. Neurosci. Res. 47, 531–538 (1997).

    CAS  PubMed  Google Scholar 

  213. Yao, D.-L., Liu, X., Hudson, L. D. & Webster, H. D. Insulin-like growth factor I treatment reduces demyelination and up-regulates gene expression of myelin-related proteins in experimental autoimmune encephalomyelitis. Proc. Natl Acad. Sci. USA 92, 6190–6194 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. O'Leary, M. T., Hinks, G. L., Charlton, H. M. & Franklin, R. J. M. Increasing local levels of IGF-I mRNA expression using adenoviral vectors does not alter oligodendrocyte remyelination in the CNS of aged rats. Mol. Cell. Neurosci. 19, 32–42 (2002).

    CAS  PubMed  Google Scholar 

  215. Cannella, B., Pitt, D., Capello, E. & Raine, C. S. Insulin-like growth factor-1 fails to enhance central nervous sytem myelin repair during autoimmune demyelination. Am. J. Pathol. 157, 933–943 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Cannella, B. et al. The neuregulin, glial growth factor 2, diminishes autoimmune demyelination and enhances remyelination in a chronic relapsing model for multiple sclerosis. Proc. Natl Acad. Sci. USA 95, 10100–10105 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Penderis, J. et al. Increasing local levels of neuregulin (glial growth factor-2) by direct infusion into areas of demyelination does not alter remyelination in the rat CNS. Eur. J. Neurosci. 18, 2253–2264 (2003).

    PubMed  Google Scholar 

  218. Fernandez, M. et al. Thyroid hormone administration enhances remyelination in chronic demyelinating inflammatory disease. Proc. Natl Acad. Sci USA 101, 16363–16368 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Franco, P. G., Silvestroff, L., Soto, E. F. & Pasquini, J. M. Thyroid hormones promote differentiation of oligodendrocyte progenitor cells and improve remyelination after cuprizone-induced demyelination. Exp. Neurol. 212, 458–467 (2008).

    CAS  PubMed  Google Scholar 

  220. Mi, S. et al. LINGO-1 negatively regulates myelination by oligodendrocytes. Nature Neurosci. 8, 745–751 (2005).

    CAS  PubMed  Google Scholar 

  221. Mi, S. et al. LINGO-1 antagonist promotes spinal cord remyelination and axonal integrity in MOG-induced experimental autoimmune encephalomyelitis. Nature Med. 13, 1228–1233 (2007).

    CAS  PubMed  Google Scholar 

  222. Rodriguez, M., Lennon, V. A., Benveniste, E. N. & Merrill, J. E. Remyelination by oligodendrocytes stimulated by antiserum to spinal cord. J. Neuropathol. Exp. Neurol. 46, 84–95 (1987).

    CAS  PubMed  Google Scholar 

  223. Miller, D. J., Sanborn, K. S., Katzmann, J. A. & Rodriguez, M. Monoclonal autoantibodies promote central nervous system repair in an animal model of multiple sclerosis. J. Neurosci. 14, 6230–6238 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Soldan, M. M. et al. Remyelination-promoting antibodies activate distinct Ca2+ influx pathways in astrocytes and oligodendrocytes: relationship to the mechanism of myelin repair. Mol. Cell. Neurosci. 22, 14–24 (2003).

    CAS  Google Scholar 

  225. Warrington, A. E. et al. Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis. Proc. Natl Acad. Sci USA 97, 6820–6825 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Confavreux, C., Hutchinson, M., Hours, M. M., Cortinovis-Tourniaire, P. & Moreau, T. Rate of pregnancy-related relapse in multiple sclerosis. Pregnancy in Multiple Sclerosis Group. N. Engl. J. Med. 339, 285–291 (1998).

    CAS  PubMed  Google Scholar 

  227. Gregg, C. et al. White matter plasticity and enhanced remyelination in the maternal CNS. J. Neurosci. 27, 1812–1823 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Chan, J. R. et al. NGF controls axonal receptivity to myelination by Schwann cells or oligodendrocytes. Neuron 43, 183–191 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  229. Ishibashi, T. et al. Astrocytes promote myelination in response to electrical impulses. Neuron 49, 823–832 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Kirby, B. B. et al. In vivo time-lapse imaging shows dynamic oligodendrocyte progenitor behavior during zebrafish development. Nature Neurosci. 9, 1506–1511 (2006). Zebrafish have only relatively recently been used to study the biology of myelination. This paper provided evidence that these lower vertebrates are likely to play a major part in future studies on myelination and remyelination.

    CAS  PubMed  Google Scholar 

  231. Hartline, D. K. & Colman, D. R. Rapid conduction and the evolution of giant axons and myelinated fibers. Curr. Biol. 17, R29–R35 (2007).

    CAS  PubMed  Google Scholar 

  232. Pogoda, H. M. et al. A genetic screen identifies genes essential for development of myelinated axons in zebrafish. Dev. Biol. 298, 118–131 (2006).

    CAS  PubMed  Google Scholar 

  233. Deloire-Grassin, M. S. et al. In vivo evaluation of remyelination in rat brain by magnetization transfer imaging. J. Neurol. Sci. 178, 10–16 (2000).

    CAS  PubMed  Google Scholar 

  234. Barkhof, F. et al. Remyelinated lesions in multiple sclerosis: magnetic resonance image appearance. Arch. Neurol. 60, 1073–1081 (2003).

    PubMed  Google Scholar 

  235. Chen, J. T. et al. Voxel-based analysis of the evolution of magnetization transfer ratio to quantify remyelination and demyelination with histopathological validation in a multiple sclerosis lesion. Neuroimage. 36, 1152–1158 (2007).

    CAS  PubMed  Google Scholar 

  236. Cailloux, F. et al. Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations. Clinical European Network on Brain Dysmyelinating Disease. Eur. J. Hum. Genet. 8, 837–845 (2000).

    CAS  PubMed  Google Scholar 

  237. Boespflug-Tanguy, O., Labauge, P. & Vaurs-Barriere, A. F. Genes involved in leukodystrophies: a glance at glial functions. Curr. Neurol. Neurosci. Rep. 8, 217–229 (2008).

    CAS  PubMed  Google Scholar 

  238. Compston, A. & Coles, A. Multiple sclerosis. Lancet 359, 1221–1231 (2002).

    PubMed  Google Scholar 

  239. Hauser, S. L. & Oksenberg, J. R. The neurobiology of multiple sclerosis: genes, inflammation, and neurodegeneration. Neuron 52, 61–76 (2006).

    CAS  PubMed  Google Scholar 

  240. Oksenberg, J. R., Baranzini, S. E., Sawcer, S. & Hauser, S. L. The genetics of multiple sclerosis: SNPs to pathways to pathogenesis. Nature Rev. Genet. 9, 516–526 (2008).

    CAS  PubMed  Google Scholar 

  241. Andlin-Sobocki, P., Jonsson, B., Wittchen, H. U. & Olesen, J. Cost of disorders of the brain in Europe. Eur. J. Neurol. 12 (Suppl. 1), 1–27 (2005).

    PubMed  Google Scholar 

  242. Haynes, R. L. et al. Oxidative and nitrative injury in periventricular leukomalacia: a review. Brain Pathol. 15, 225–233 (2005).

    CAS  PubMed  Google Scholar 

  243. Back, S. A. et al. Late oligodendrocyte progenitors coincide with the developmental window of vulnerability for human perinatal white matter injury. J. Neurosci. 21, 1302–1312 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  244. Peters, A. & Sethares, C. Oligodendrocytes, their progenitors and other neuroglial cells in the aging primate cerebral cortex. Cereb. Cortex 14, 995–1007 (2004).

    PubMed  Google Scholar 

  245. Belachew, S. et al. Postnatal NG2 proteoglycan-expressing progenitor cells are intrinsically multipotent and generate functional neurons. J. Cell Biol. 161, 169–186 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  246. Kondo, T. & Raff, M. Oligodendrocyte precursor cells reprogrammed to become multipotential CNS stem cells. Science 289, 1754–1757 (2000).

    CAS  PubMed  Google Scholar 

  247. Gaughwin, P. M. et al. Astrocytes promote neurogenesis from oligodendrocyte precursor cells. Eur. J. Neurosci. 23, 945–956 (2006).

    CAS  PubMed  Google Scholar 

  248. Alonso, G. NG2 proteoglycan-expressing cells of the adult rat brain: possible involvement in the formation of glial scar astrocytes following stab wound. Glia 49, 318–338 (2005).

    CAS  PubMed  Google Scholar 

  249. Cassiani-Ingoni, R. et al. Cytoplasmic translocation of Olig2 in adult glial progenitors marks the generation of reactive astrocytes following autoimmune inflammation. Exp. Neurol. 201, 349–358 (2006).

    CAS  PubMed  Google Scholar 

  250. Talbott, J. F. et al. Schwann cell-like differentiation by adult oligodendrocyte precursor cells following engraftment into the demyelinated spinal cord is BMP-dependent. Glia 54, 147–159 (2006).

    PubMed  PubMed Central  Google Scholar 

  251. Blakemore, W. F. Invasion of Schwann cells into the spinal cord of the rat following local injections of lysolecithin. Neuropathol. Appl. Neurobiol. 2, 21–39 (1976).

    Google Scholar 

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Acknowledgements

The authors are very grateful to R. Karadottir, A. Williams and M. Zawadzka, and to the members of both the Franklin and the ffrench-Constant laboratories for their critical input and to C. Zhao for his contributions to figure 2.

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Authors and Affiliations

  1. Department of Veterinary Medicine and Cambridge Centre for Brain Repair, University of Cambridge, Madingley Road, Cambridge, CB3 0ES, UK

    Robin J. M. Franklin

  2. MRC Centre for Regenerative Medicine and MS Society/University of Edinburgh Centre for Translational Research, Centre for Inflammation Research, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ, UK

    Charles ffrench-Constant

  3. Charles ffrench-Constant

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Glossary

Oligodendrocyte

The myelin-forming cell of the CNS.

Oligodendroglia

Cells of the oligodendrocyte lineage, such as precursor cells and more-differentiated myelin-forming cells.

Cuprizone-induced demyelination model

A model of demyelination induced by chronic oral administration of the copper chelator cuprizone. Cuprizone is toxic for oligodendrocytes, and the model, like the ethidium bromide model of demyelination, partly mimics a form of MS in which oligodendrocyte apoptosis predominates. Remyelination occurs following removal of the toxin from the diet.

Experimental autoimmune encephalomyelitis

(EAE). An inflammatory disease of the CNS that is generated by inducing an immune response to myelin components such as myelin-oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP). This induction protocol is most commonly applied in rodents and used as a model to study MS.

Oligodendrocyte precursor cell

(OPC). The precursor cell that generates oligodendrocytes in the CNS. They themselves are generated in restricted, stem-cell-containing regions of the CNS, from where they migrate extensively to the axon tracts that become myelinated. They persist into adulthood and are the cells that are responsible for remyelination.

Heterochronic parabiosis

The anastomosis of the circulation of two animals of different ages, to determine whether the presence or absence of factors in the bloodstream is responsible for any changes associated with aging, such as diminished repair capacity.

Theiler's virus-induced demyelination model

A model of demyelination induced by infecting susceptible mouse strains with Theiler's murine encephalitis virus. Demyelination occurs after the acute phase of the disease where viral replication occurs in the CNS, and is associated with viral persistence. The mechanisms of demyelination are thought to include autoimmune destruction of myelin and bystander damage caused by the chronic inflammation in the CNS.

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Franklin, R., ffrench-Constant, C. Remyelination in the CNS: from biology to therapy. Nat Rev Neurosci 9, 839–855 (2008). https://doi.org/10.1038/nrn2480

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