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Regenerating CNS myelin — from mechanisms to experimental medicines

Key Points

  • Remyelination is a spontaneous regenerative process in the adult mammalian CNS in which new oligodendrocytes and myelin sheaths are generated from a widespread population of adult progenitor cells.

  • Remyelination involves the distinct stages of progenitor activation, recruitment (proliferation and migration) and differentiation into mature myelin-sheath-forming oligodendrocytes: each is orchestrated by a complex network of cells and signalling molecules.

  • The efficiency of remyelination declines progressively with adult ageing, a phenomenon that has a profound bearing on the natural history of chronic demyelinating diseases such as multiple sclerosis, although experimental studies have revealed that the effects of age are reversible.

  • Remyelination is neuroprotective, limiting the axonal degeneration that follows demyelination. Restoring remyelination is therefore an important therapeutic goal so as to prevent neurodegeneration and progressive disability in multiple sclerosis and other myelin diseases.

  • Insights into the mechanism governing remyelination and an increasing number of high-throughput screening platforms have led to the identification of a number of drug targets for the pharmacological enhancement of remyelination, some of which have entered clinical trials.

  • Advances in the generation of large numbers of human stem and progenitor cells, coupled with compelling preclinical data, have opened up new opportunities for cell-based remyelination therapies, especially for the leucodystrophies.

Abstract

Although the core concept of remyelination — based on the activation, migration, proliferation and differentiation of CNS progenitors — has not changed over the past 20 years, our understanding of the detailed mechanisms that underlie this process has developed considerably. We can now decorate the central events of remyelination with a host of pathways, molecules, mediators and cells, revealing a complex and precisely orchestrated process. These advances have led to recent drug-based and cell-based clinical trials for myelin diseases and have opened up hitherto unrecognized opportunities for drug-based approaches to therapeutically enhance remyelination.

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Figure 1: The logic of promoting remyelination.
Figure 2: The biology of remyelination.
Figure 3: The architecture of remyelination.
Figure 4: Drug discovery for remyelination.

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Both authors researched the data for the article, provided a substantial contribution to discussion of content, wrote the article and reviewed and edited the manuscript before submission.

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Glossary

Oligodendrocytes

The cells that make myelin in the CNS. A single oligodendrocyte can make up to 80 separate myelin sheaths, although approximately 10–20 is more usual.

Remyelination

The regenerative process involving the generation of new oligodendrocytes from CNS-resident progenitor cells and the formation of new myelin sheaths around the demyelinated axon.

Multiple sclerosis

(MS). A common autoimmune-mediated disease of the CNS that is characterized by multiple acute inflammatory foci involving immune-mediated demyelination that can undergo spontaneous remyelination; with disease progression, this remyelination becomes less efficient, leaving axons chronically demyelinated and prone to irreversible degeneration.

Demyelination

The pathological process in which myelin sheaths are lost from axons that remain intact. It is sometimes called primary demyelination to distinguish it from loss of myelin that is secondary to axonal loss, which is more accurately called Wallerian degeneration and should not be called demyelination.

Schwann cells

The cells that make myelin in the peripheral nervous system. A single Schwann cell only ever makes a single myelin sheath. In certain circumstances, Schwann cells can remyelinate demyelinated axons in the CNS.

g ratio

The ratio of the axon diameter to the diameter of the myelinated axon; this term is used to provide a quantitative measure of the myelin sheath thickness compared with the axon diameter. In remyelination, the g ratio usually increases.

Leucodystrophies

A family of genetic diseases usually characterized by inadequate myelination or demyelination.

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Franklin, R., ffrench-Constant, C. Regenerating CNS myelin — from mechanisms to experimental medicines. Nat Rev Neurosci 18, 753–769 (2017). https://doi.org/10.1038/nrn.2017.136

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