Elsevier

Brain Research Bulletin

Volume 49, Issue 6, August 1999, Pages 377-391
Brain Research Bulletin

Review Article
The glial scar and central nervous system repair

https://doi.org/10.1016/S0361-9230(99)00072-6Get rights and content

Abstract

Damage to the central nervous system (CNS) results in a glial reaction, leading eventually to the formation of a glial scar. In this environment, axon regeneration fails, and remyelination may also be unsuccessful. The glial reaction to injury recruits microglia, oligodendrocyte precursors, meningeal cells, astrocytes and stem cells. Damaged CNS also contains oligodendrocytes and myelin debris. Most of these cell types produce molecules that have been shown to be inhibitory to axon regeneration. Oligodendrocytes produce NI250, myelin-associated glycoprotein (MAG), and tenascin-R, oligodendrocyte precursors produce NG2 DSD-1/phosphacan and versican, astrocytes produce tenascin, brevican, and neurocan, and can be stimulated to produce NG2, meningeal cells produce NG2 and other proteoglycans, and acitivated microglia produce free radicals, nitric oxide, and arachidonic acid derivatives. Many of these molecules must participate in rendering the damaged CNS inhibitory for axon regeneration. Demyelinated plaques in multiple sclerosis consists mostly of scar-type astrocytes and naked axons. The extent to which the astrocytosis is responsible for blocking remyelination is not established, but astrocytes inhibit the migration of both oligodendrocyte precursors and Schwann cells which must restrict their access to demyelinated axons.

Introduction

Whenever the central nervous system (CNS) is damaged it undergoes an injury response, usually called reactive gliosis or glial scarring. The response is broadly the same whatever the source of the injury, although the details vary somewhat with different types of pathology. The consequence is that after the initial period of cell death and damage, during which neuroprotective and glioprotective treatments are the main therapeutic aim, any form of treatment designed to repair CNS damage, whether it be designed to make axons regenerate, induce remyelination, or to replace dead neurones, will inevitably have to take place in a glial scar environment. Since there is evidence that glial scars can inhibit both axon growth and myelination, it is clearly important to know what causes them to form, what cells are involved, why they are inhibitory, and how to manipulate them.

Section snippets

The CNS reaction to injury

CNS damage initiates a series of cellular and molecular events that evolve over several days. The main cell types involved in these changes are astrocytes, microglia, and oligodendrocyte precursors, with some involvement of meningeal cells and stem cells. The glial scar is an evolving structure, with different cells arriving and participating at different times. The first cells to arrive in a CNS injury are macrophages from the bloodstream and microglia migrating in from the surrounding tissue,

The glial scar and axon regeneration

A major cause of the failure of axon regeneration in the CNS is the inhibitory nature of the glial environment. However, set against this it should be remembered that the regenerative ability of most CNS axons is very low 53, 194, so even fairly minor degrees of inhibition are probably sufficient to prevent regeneration. Since damage to CNS axons will always produce a glial scar, the place where regeneration of axons fails inevitably contains a developing or established glial scar. All the five

Which molecules are inhibitory in CNS lesions?

From the preceding sections, it should be clear that the damaged CNS is potentially awash with inhibitory molecules derived from several cell types. Which of these might actually be preventing axon regeneration?. In order to be a serious contender, a molecule must have demonstrable inhibitory activity, and be present in CNS injury sites at the time when axons are attempting to regenerate. Our knowledge of which of the molecules discussed above is upregulated in the damaged CNS is incomplete,

The glial scar and remyelination

Remyelination is a complex topic. Unlike axonal regeneration, remyelination in the mammalian CNS can occur after many types of pathology. The CNS contains large numbers of oligodendrocyte precursors which are capable of remyelination, and Schwann cells when they invade the CNS are also capable of remyelinating CNS axons. However, remyelination is by no means always successful, and it fails particularly in multiple sclerosis (MS). It is not the purpose of this article to review the biology of

Conclusion

The glial scar, or reactive gliosis, is the environment in which spontaneous CNS repair succeeds, or more often fails, and the environment with which any therapeutic efforts will have to contend. The complexity of the structure, and the large number of molecules within it that have effects on repair processes are somewhat daunting. It will be necessary to develop techniques to control the recruitment of the different cell types, by influencing cell division, migration, or by killing some cells.

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