Review ArticleThe glial scar and central nervous system repair
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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