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Remyelination in the CNS: from biology to therapy

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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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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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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