The Role of Oligodendrocytes and Oligodendrocyte Progenitors in cns Remyelination

  • Hans S. Keirstead
  • William F. Blakemore

Abstract

Remyelination enables restoration of saltatory conduction and a return of normal function lost during demyelination. Unfortunately, remyelination is often incomplete in the adult human central nervous system (CNS) and this failure of remyelination is one of the main reasons for clinical deficits in demyelinating disease. An understanding of the failure of remyelination in demyelinating diseases such as Multiple Sclerosis depends upon the elucidation of cellular events underlying successful remyelination. Although the potential for remyelination of the adult CNS has been well established, there is still some dispute regarding the origin of the remyelinating cell population. The literature variously reports that remyelinating oligodendrocytes arise from dedifferentiation and/or proliferation of mature oligodendrocytes, or are generated solely from proliferation and differentiation of glial progenitor cells. This review focuses on studies carried out on remyelinating lesions in the adult rat spinal cord produced by injection of antibodies to galactocerebroside plus serum complement that demonstrate: 1) oligodendrocytes which survive within an area of demyelination do not contribute to remyelination, 2) remyelination is carried out by oligodendrocyte progenitor cells, 3) recruitment of oligodendrocyte progenitors to an area of demyelination is a local response, and 4) division of oligodendrocyte progenitors is symmetrical and results in chronic depletion of the oligodendrocyte progenitor population in the normal white matter around an area of remyelination. These results suggest that failure of remyelination may be contributed to by a depletion of oligodendrocyte progenitors especially following repeated episodes of demyelination.

Remyelination allows the return of saltatory conduction (Smith et al., 1979) and the functional recovery of demyelination-induced deficits (Jeffery et al., 1997). Findings such as these have encouraged research aimed at enhancing the limited remyelination found in Multiple Sclerosis (MS) lesions, evidenced by a rim of thin myelin sheaths around the edges of a lesion, or, in a minority of acute foci, throughout the entire lesion (Prineas et al., 1989; Raine et al., 1981). It must be said, however, that although remyelination is clearly a prerequisite to sustained functional recovery, other factors such as the state of the inflammatory response and degree of axonal survival within the demyelinated region contribute to the extent of functional recovery that may be possible following therapeutic intervention aimed at halting disease progression. It is not yet clear whether the progression of functional deficits in MS is primarily the result of an increasing load of demyelination, or axon loss, or a combination of the two processes. However, given the increasing recognition that myelin sheaths playa role in protecting axons from degeneration, the success or failure of remyelination has functional consequences for the patient.

To understand why remyelination should fail in demyelinating disease and develop strategies to enhance remyelination requires an understanding of the biology of successful remyelination. Firstly, what is the origin of the remyelinating cell population in the adult CNS? Secondly, what are the dynamics of the cellular response of this population during demyelination and remyelination? And thirdly, what are the consequences to the tissue of an episode of demyelination? This review will focus on studies that address these issues, and discuss the implications of the results of these experiments for our understanding of MS and the development of therapeutic interventions aimed at enhancing remyelination.

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References

  1. Arenella LS and Herndon RM (1984) Mature oligodendrocytes: division following experimental demyelination in adult animals. Arch Neurol 41: 1162–1165.PubMedCrossRefGoogle Scholar
  2. Armstrong RC, Dorn HH, Kufta CV, Friedman E, and Dubois-Dalcq ME (1992) Pre-oligodendrocytes from Adult Human CNS. J Neurosci 12: 1538–1547.PubMedGoogle Scholar
  3. Arvanitis B, Polak PE, and Szuchet S (1992) Myelin palinogenesis. 1. Electron microscopical localisation of myelin/oligodendrocyte proteins in multilamellar structures by the immunogold method. Dev Neurosci 14: 313–327.PubMedCrossRefGoogle Scholar
  4. Bansal R and Pfeiffer SE (1997) FGF-2 converts mature oligodendrocytes to a novel phenotype. J Neurosci Res 50: 215–228.PubMedCrossRefGoogle Scholar
  5. Barres BA, Hart IK, Coles HSR, Burne JF, Voyvodic JT, Richardson WD, and Raff MC (1992) Cell death in the oligodendrocyte lineage. J Neurobiol 23: 1221–1230.PubMedCrossRefGoogle Scholar
  6. Berger T and Frotscher M (1994) Distribution and morphological characteristics of oligodendrocytes in the rat hippocampus in situand in vitro: An immunocytochemical study with the monoclonal Rip antibody. J Neurocytol 23: 61–74.PubMedCrossRefGoogle Scholar
  7. Blakemore WF (1972) Observations on oligodendrocyte degeneration, the resolution of status spongiosus and remyelination in cuprizone intoxication in mice. J Neurocytol 1: 413–426.PubMedCrossRefGoogle Scholar
  8. Blakemore WF (1973) Demyelination of the superior cerebellar peduncle in the mouse induced by cuprizone. J Neurol Sci 20: 63–72.PubMedCrossRefGoogle Scholar
  9. Blakemore WF and Patterson RC (1978) Suppression of remyelination in the CNS by x-irradiation. Acta Neuropathol 42: 105–113.PubMedCrossRefGoogle Scholar
  10. Blakemore WF, Crang AJ, and Franklin RJM (1995a) Transplantation of glial cells. In BR Ransom and H Kettenmann (Eds), Neuroglia, Oxford University Press, New York, pp. 869–882.Google Scholar
  11. Blakemore WF and Keirstead HS (1998) The origin of remyelinating cells in the adult CNS. J Neuroimmunol (in press)Google Scholar
  12. Bologa L, Z’Graggen A, Rossi E, and Herschkowitz N (1982) Differentiation and proliferation: two possible mechanisms for the regeneration of oligodendrocytes in culture. J Neurol Sci 57: 419–434.PubMedCrossRefGoogle Scholar
  13. Brück W, Schmied M, Suchanek G., Brück Y, Breitschopf H, Poser S, Piddlesden S, and Lassmann H (1994) Oligodendrocytes in the early course of multiple sclerosis. Annal Neurol 35: 65–73.PubMedCrossRefGoogle Scholar
  14. Carroll WM and Jennings AR (1994) Early recruitment of oligodendrocyte precursors in CNS demyelination. Brain 117: 563–578.PubMedCrossRefGoogle Scholar
  15. Carroll WM, Jennings AR, and Mastaglia FL (1990) The origin of remyelinating oligodendrocytes in antiserum-mediated demyelinative optic neuropathy. Brain 113: 953–973.PubMedCrossRefGoogle Scholar
  16. Carroll WM, Jennings AR, and Iornside LJ (1998) Identification of the adult resting progenitor cell by autoradiographic tracking of oligodendrocyte precursors in experimental CNS demyelination. Brain 121: 293–302.PubMedCrossRefGoogle Scholar
  17. Crang AJ, Gilson J, and Blakemore WF (1998) The demonstration by transplantation of the limited remyelinating potential of post mitotic oligodendrocytes. J Neurocytol (in press).Google Scholar
  18. French-Constant C and Raff MC (1986) Proliferating bipotential glial progenitor cells in adult optic nerve. Nature 319: 499–502.CrossRefGoogle Scholar
  19. Franklin RJM, Crang AJ, and Blakemore WF (1993) The reconstruction of an astrocytic environment in gliadeficient areas of white matter. J Neurocytol 22: 382–396.PubMedCrossRefGoogle Scholar
  20. Franklin RJM and Blakemore WF (1997a) Transplanting oligodendrocyte progenitors into the adult CNS. JAnat 190: 23–33.Google Scholar
  21. Franklin RJM, Gilson JM, and Blakemore WF (1997b) Local recruitment of remyelinating cells in the repair of demyelination in the central nervous system. J Neurosci Res 50: 244–337.Google Scholar
  22. Friedman B, Hockfield S, Black JA, Woodruff KA, and Waxman SG (1989) In situ demonstration of mature oligodendrocytes and their processes: an immunohistochemical study with a new monoclonal antibody, Rip. Glia 2: 390.Google Scholar
  23. Gensert JM and Goldman JE (1997) Endogenous progenitors remyelinate demyelinated axons in the adult CNS. Neuron 19: 197–203.PubMedCrossRefGoogle Scholar
  24. Gogate N, Verma L, Zhou JM, Milward E, Rusten R, O’Connor M, Kufta C, Kim J, Hudson L, and Dubois-Dalcq M (1994) Plasticity in the adult human oligodendrocyte lineage. J Neurosci 14: 4571–4587.PubMedGoogle Scholar
  25. Groves AK, Barnett SC, Franklin RJM, Crang AJ, Mayer M, Blakemore WF, and Noble M (1993) Repair of demyelinated lesions by transplantation of purified O-2A progenitor cells. Nature 362: 453–455.PubMedCrossRefGoogle Scholar
  26. Hardy R and Reynolds R (1991) Proliferation and differentiation potential of rat forebrain oligodendroglial progenitors both in vitro and in vivo. Development 4: 1061–1080.Google Scholar
  27. Hardy RJ and Friedrick VL (1996) Oligodendrocyte progenitors are generated throughout the embryonic mouse brain, but differentiate in restricted foci. Development 122: 2059–2069.PubMedGoogle Scholar
  28. Hunter SF and Bottenstein JE (1991) O-2A glial progenitors from mature brain respond to CNS neuronal cell line-derived growth factors. J Neurosci Res 4: 574–582.CrossRefGoogle Scholar
  29. Jeffery ND and Blakemore WF (1997) Locomotor deficits induced by experimental spinal cord demyelination are abolished by spontaneous remyelination. Brain 120: 27–37.PubMedCrossRefGoogle Scholar
  30. Johnson ES and Ludwin SK (1981) The demonstration of recurrent demyelination and remyelination of axons in the central nervous system. Acta Neuropathol 53: 93–98.PubMedCrossRefGoogle Scholar
  31. Keirstead HS and Blakemore WF (1997) Identification of post-mitotic oligodendrocytes incapable of remyelination within the demyelinated adult spinal cord. J Neuropath Exp Neurol 56: 1191–1201.PubMedCrossRefGoogle Scholar
  32. Keirstead HS, Levine JM, and Blakemore WF (1998) Response of the oligodendrocyte progenitor cell population (defined by NG2 labelling) to demyelination in the adult spinal cord. Glia 22: 161–170.PubMedCrossRefGoogle Scholar
  33. Lassmann H (1983) Chronic relapsing experimental allergic encephalomyelitis: Its value as an experimental model for multiple sclerosis. J Neurol 4: 207–220.CrossRefGoogle Scholar
  34. Levine JM and Stallcup WB (1987) Plasticity of developing cerebellar cells in vitro studied with antibodies against the NG2 antigen. J Neurosci 2721–2731.Google Scholar
  35. Levison SW and Goldman JE (1993) Both oligodendrocytes and astrocytes develop from progenitors in the subventricular zone of postnatal rat forebrain. Neuron 2: 201–212.CrossRefGoogle Scholar
  36. Li Y, Chopp M, Powers C, and Jiang N (1997) Immunoreactivity of cyclin Dl/cdk4 in neurons and oligodendrocytes after focal cerebral ischemia in rat. J Cereb Blood Flow Metab 17: 846–856.PubMedCrossRefGoogle Scholar
  37. Ludwin SK (1978) Central nervous system demyelination and remyelination in the mouse. An ultrastructural study of cuprizone toxicity Lab Invest 39: 597–612.Google Scholar
  38. Ludwin SK (1979) An autoradiographic study of cellular proliferation in remyelination of the central nervous system. Am J Pathol 65: 683–696.Google Scholar
  39. Ludwin SK (1984) Proliferation of mature oligodendrocytes after trauma to the central nervous system. Nature 308: 274–275.PubMedCrossRefGoogle Scholar
  40. Ludwin SK, and Bakker DA (1988) Can oligodendrocytes attached to myelin proliferate. J Neurosci 8: 1239–1244.PubMedGoogle Scholar
  41. Ludwin SK and Szuchet S (1993) Myelination by mature ovine oligodendrocytes in vivo and in vitro: evidence that different steps in the myelination process are independently controlled. Glia 8: 219–231.PubMedCrossRefGoogle Scholar
  42. Muir DA and Compston DAS (1996) Growth factor stimulation triggers apoptotic cell death in mature oligodendrocytes. J Neurosci Res 44: 1–11.PubMedCrossRefGoogle Scholar
  43. Nait-Oumesmar B, Vignais L, Duhamel-Clérin E, Avellana-Adalid V, Rougon G., and Baron-Van Evercooren A (1995) Expression of the highly polysialylated neural cell adhesion molecule during postnatal myelination and following chemically induced demyelination of the adult mouse spinal cord. Eur J Neurosci 7: 480–491.PubMedCrossRefGoogle Scholar
  44. Noll E and Miller RH (1993) Oligodendrocyte precursors originate at the ventral ventricular zone dorsal to the ventral midline region in the embryonic rat spinal cord. Development 2: 563–573.Google Scholar
  45. O’Leary M and Blakemore WF (1997) Use of a rat Y chromosome probe to determine the long-term survival of glial cells transplanted into areas of CNS demyelination. J Neurocytol 26: 191–206.CrossRefGoogle Scholar
  46. Ozawa K, Suchanek G., Breitschopf H, Brück W, Budka H, Jellinger K, and Lassmann H (1994) Patterns of oligodendroglia pathology in multiple sclerosis. Brain 117: 1311–1322.PubMedCrossRefGoogle Scholar
  47. Prayoonwiwat N and Rodriguez M (1993) The potential for oligodendrocyte proliferation during demyelinating disease. J Neuropath Exp Neurol 52: 55–63.PubMedCrossRefGoogle Scholar
  48. Prineas JW, Kwon EE, Goldenberg PZ, Ilyas AA, Quarles RH, Benjamins JA, and Sprinkle TJ (1989) Multiple sclerosis: oligodendrocyte proliferation and differentiation in fresh lesions. Lab Invest 61: 489–503.PubMedGoogle Scholar
  49. Pringle NP and Richardson WD (1993) A singularity of PDGF alpha-receptor expression in the dorsoventral axis of the neural tube may define the origin of the oligodendrocyte lineage. Development 2: 525–533.Google Scholar
  50. Raine CS, Scheinberg L, and Waltz JM (1981) Multiple sclerosis: Oligodendrocyte survival and proliferation in an active established lesion. Lab Invest 45: 534–546.PubMedGoogle Scholar
  51. Reynolds R and Hardy R (1997) Oligodendroglial progenitors labeled with the O4 antibody persist in the adult rat cerebral cortex in vivo. J Neurosci Res 47: 455–470.PubMedCrossRefGoogle Scholar
  52. Rodriguez M and Lennon VA (1990) Immunogloulins promote remyelination in the central nervous system. Annal Neurol 27: 12–17.PubMedCrossRefGoogle Scholar
  53. Rodriguez M, Pierce ML, and Thiemann RL (1991) Immunoglobulins stimulate central nervous system remyelination: electron microscopic and morphometric analysis of proliferating cells. Lab Invest 64: 358–370.PubMedGoogle Scholar
  54. Scolding NJ, Rayner PJ, Sussman J, Shaw C, and Compston DAS (1995) A proliferative adult human oligodendrocyte progenitor. NeuroReport 6: 441–445.PubMedCrossRefGoogle Scholar
  55. Skoff RP and Knapp PE (1991) Division of astroblasts and oligodendroblasts in postnatal rRodent brainevidence for separate astrocyte and oligodendrocyte lineages. Glia 4: 165–174.PubMedCrossRefGoogle Scholar
  56. Smith KJ, Blakemore WF, and McDonald WI (1979) Central remyelination restores secure conduction. Nature 280: 395–396.PubMedCrossRefGoogle Scholar
  57. Targett MP, Sussman J, O’Leary MT, Compston DAS, and Blakemore WF (1996) Failure to achieve remyelination of demyelinated rat axons following transplantation of glial cells obtained from the adult human brain. Neuropath Appl Neurobiol 22: 199–206.CrossRefGoogle Scholar
  58. Wolswijk G and Noble M (1989) Identification of an adult-specific glial progenitor cell. Development 105: 387–400.PubMedGoogle Scholar
  59. Wolswijk G and Noble M (1992) Cooperation between PDGF and FGF converts slowly dividing 0-2Aadultprogenitor cells to rapidly dividing cells with characteristics of O-2APerinatal progenitor cells. J Cell Biol 118: 889–900.PubMedCrossRefGoogle Scholar
  60. Wolswijk G., Riddle PN, and Noble M (1990) Coexistence of perinatal and adult forms of a glial progenitor cell during development of the rat optic nerve. Development 109: 691–698.PubMedGoogle Scholar
  61. Wood PM and Bunge RP (1986) Evidence that axons are mitogenic for oligodendrocytes isolated from adult animals. Nature 320: 756–758.PubMedCrossRefGoogle Scholar
  62. Woodruff RH and Franklin RJM (1997) Growth factors and remyelination in the CNS. Histol Histopath 12: 459–466.Google Scholar
  63. Wren D, Wolswijk G., and Noble M (1992) In vitro analysis of the origin and maintenance of O-2Aadult progenitor cells. J Cell Biol 116: 167–176.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Hans S. Keirstead
    • 1
  • William F. Blakemore
    • 1
    • 2
  1. 1.MRC Cambridge Centre for Brain Repair and Department of Clinical Veterinary MedicineUniversity of Cambridge Robinson WayCambridgeUK
  2. 2.Department of Clinical Veterinary MedicineCambridgeUK

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