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The biology of CNS remyelination

The key to therapeutic advances

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Abstract

Remyelination, the process by which new myelin sheaths are restored to demyelinated axons, represents one of the most compelling examples of adult multipotent progenitor cells contributing to regeneration of the injured CNS. This process can occur with remarkable efficiency in both clinical disease, such as multiple sclerosis, and in experimental models, revealing an impressive ability of the adult CNS to repair itself. However, the inconsistency of remyelination in multiple sclerosis, and the loss of axonal integrity that results from its failure, makes enhancement of remyelination an important therapeutic objective. Identifying potential targets requires a detailed understanding of the cellular and molecular mechanisms of remyelination. A critical step in achieving effective remyelination is the differentiation of precursor cells into mature oligodendrocytes. In experimental models of demyelinating disease in aged animals, as well as in multiple sclerosis, such differentiation appears to be impaired. This is due, at least in part, to changes in environmental signals governing remyelination. In particular, myelin debris within lesions appears to contain powerful inhibitors of precursor cell differentiation. Efficient removal of myelin debris by macrophages may thus facilitate differentiation and permit successful remyelination of damaged axons. This may represent a promising therapeutic target for promoting remyelination in multiple sclerosis and thus limiting the accumulation of irreversible neurological disability.

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References

  1. Barnes D, Munro PM, Youl BD, Prineas JW, McDonald WI (1991) The longstanding MS lesion. A quantitative MRI and electron microscopic study. Brain 114(Pt 3):1271–1280

    Article  PubMed  Google Scholar 

  2. Ben-Hur T, Einstein O, Mizrachi-Kol R, Ben-Menachem O, Reinhartz E, Karussis D, Abramsky O (2003) Transplanted multipotential neural precursor cells migrate into the inflamed white matter in response to experimental auto immune encephalomyelitis. Glia 41:73–80

    Article  PubMed  Google Scholar 

  3. Chang A, Tourtellotte WW, Rudick R, Trapp BD (2002) Premyelinating oligodendrocytes in chronic lesions of multiple sclerosis. The New England Journal of Medicine 346:165–173

    Article  PubMed  Google Scholar 

  4. Einstein O, Fainstein N, Vaknin I, Mizrachi-Kol R, Reihartz E, Grigoriadis N, Lavon I, Baniyash M, Lassmann H, Ben-Hur T (2007) Neural precursors attenuate autoimmune encephalomyelitis by peripheral immunosuppression. Ann Neurol 61:209–218

    Article  PubMed  CAS  Google Scholar 

  5. Einstein O, Grigoriadis N, Mizrachi-Kol R, Reinhartz E, Polyzoidou E, Lavon I, Milonas I, Karussis D, Abramsky O, Ben-Hur T (2006) Transplanted neural precursor cells reduce brain inflammation to attenuate chronic experimental auto immune encephalomyelitis. Exp Neurol 198:275–284

    Article  PubMed  CAS  Google Scholar 

  6. Hinks GL, Franklin RJM (2000) Delayed changes in growth factor gene expression during slow remyelination in the CNS of aged rats. Mol Cell Neurosci 16:542–556

    Article  PubMed  CAS  Google Scholar 

  7. Ibanez C, Shields SA, El-Etr M, Baulieu EE, Schumacher M, Franklin RJM (2004) 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

    Article  PubMed  CAS  Google Scholar 

  8. Kotter MR, Li WW, Zhao C, Franklin RJM (2006) Myelin impairs CNS remyelination by inhibiting oligodendrocyte precursor cell differentiation. J Neurosci 26:328–332

    Article  PubMed  CAS  Google Scholar 

  9. Kotter MR, Setzu A, Sim FJ, Van Rooijen N, Franklin RJM (2001) Macrophage depletion impairs oligodendrocyte remyelination following lysolecithin-induced demyelination. Glia 35:204–212

    Article  PubMed  CAS  Google Scholar 

  10. Kotter MR, Zhao C, van Rooijen N, Franklin RJM (2005) Macrophagedepletion 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

    Article  PubMed  CAS  Google Scholar 

  11. Lappe-Siefke C, Goebbels S, Gravel M, Nicksch E, Lee J, Braun PE, Griffiths IR, Nave KA (2003) Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination. Nature Genetics 33:366–374

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  14. Patrikios P, Stadelmann C, Kutzelnigg A, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Bruck W, Lucchinetti C, Lassmann H (2006) Remyelination is extensive in a subset of multiple sclerosis patients. Brain 129:3165–3172

    Article  PubMed  Google Scholar 

  15. Pluchino S, Martino G (2005) The therapeutic use of stem cells for myelin repair in autoimmune demyelinating disorders. J Neurol Sci 233:117–119

    Article  PubMed  CAS  Google Scholar 

  16. Pluchino S, Quattrini A, Brambilla E, Gritti A, Salani G, Dina G, Galli R, Del Carro U, Amadio S, Bergami A, Furlan R, Comi G, Vescovi AL, Martino G (2003) Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis. Nature 422:688–694

    Article  PubMed  CAS  Google Scholar 

  17. Prineas JW, Barnard RO, Kwon EE, Sharer LR, Cho ES (1993) Multiple sclerosis: remyelination of nascent lesions. Ann Neurol 33:137–151

    Article  PubMed  CAS  Google Scholar 

  18. Prineas JW, Connell F (1978) The fine structure of chronically active multiple sclerosis plaques. Neurology 28:68–75

    PubMed  CAS  Google Scholar 

  19. Prineas JW, Kwon EE, Cho ES, Sharer LR (1984) Continual breakdown and regeneration of myelin in progressive multiple sclerosis plaques. Ann NY Acad Sci 436:11–32

    Article  PubMed  CAS  Google Scholar 

  20. Prineas JW, Kwon EE, Goldenberg PZ, Cho ES, Sharer LR (1990) Interaction of astrocytes and newly formed oligodendrocytes in resolving multiple sclerosis lesions. Laboratory Investigation; a Journal of Technical Methods and Pathology 63:624–636

    PubMed  CAS  Google Scholar 

  21. Robinson S, Miller RH (1999) Contact with central nervous system myelin inhibits oligodendrocyte precursor maturation. Devel Biol 216:359–368

    Article  CAS  Google Scholar 

  22. Shields SA, Gilson JM, Blakemore WF, Franklin RJM (1999) Remyelination occurs as extensively but more slowly in old rats compared to young rats following gliotoxin-induced CNS demyelination. Glia 28:77–83

    Article  PubMed  CAS  Google Scholar 

  23. Sim FJ, Hinks GL, Franklin RJM (2000) The re-expression of the homeodomain transcription factor Gtx during remyelination of experimentally induced demyelinating lesions in young and old rat brain. Neuroscience 100:131–139

    Article  PubMed  CAS  Google Scholar 

  24. Sim FJ, Zhao C, Penderis J, Franklin RJM (2002) 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

    PubMed  CAS  Google Scholar 

  25. Smith PM, Jeffery ND (2006) Histological and ultrastructural analysis of white matter damage after naturally-occurring spinal cord injury. Brain Pathol (Zurich, Switzerland) 16:99–109

    Article  PubMed  Google Scholar 

  26. van Rooijen N, van Nieuwmegen R (1984) Elimination of phagocytic cells in the spleen after intravenous injection of liposome-encapsulated dichloromethylene diphosphonate. An enzyme-histochemical study. Cell and Tissue Research 238:355–358

    Article  PubMed  CAS  Google Scholar 

  27. Wolswijk G (1998) Chronic stage multiple sclerosis lesions contain a relatively quiescent population of oligodendrocyte precursor cells. J Neurosci 18:601–609

    PubMed  CAS  Google Scholar 

  28. Woodruff RH, Franklin RJM (1999) 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

    Article  PubMed  CAS  Google Scholar 

  29. Woodruff RH, Fruttiger M, Richardson WD, Franklin RJM (2004) Platelet-derived growth factor regulates oligodendrocyte progenitor numbers in adult CNS and their response following CNS demyelination. Mol Cell Neurosci 25:252–262

    Article  PubMed  CAS  Google Scholar 

  30. Yajima K, Suzuki K (1979) Demyelination and remyelination in the rat central nervous system following ethidium bromide injection. Laboratory Investigation; a Journal of Technical Methods and Pathology 41:385–392

    PubMed  CAS  Google Scholar 

  31. Zhao C, Li WW, Franklin RJM (2006) 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

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Dept. of Veterinary Medicine, University of Cambridge, Madingely Road, Cambridge, CB3 0ES

    Robin J. M. Franklin & Mark R. Kotter

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  1. Robin J. M. Franklin
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  2. Mark R. Kotter
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Correspondence to Robin J. M. Franklin.

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Franklin, R.J.M., Kotter, M.R. The biology of CNS remyelination. J Neurol 255 (Suppl 1), 19–25 (2008). https://doi.org/10.1007/s00415-008-1004-6

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  • DOI: https://doi.org/10.1007/s00415-008-1004-6

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