Inflammation stimulates myelination by transplanted oligodendrocyte precursor cells.

Inflammation associated with CNS demyelination provides an important stimulus for the activation of endogenous oligodendrocyte precursor cells (OPCs) and subsequent remyelination. This view is largely based on "loss-of-function" studies, whereby remyelination is impaired following depletion of inflammatory cells or mediators. However, "gain-of-function" approaches, asking whether inflammation directly enhances remyelination, have received less attention. We have addressed this issue using a model in which OPCs transplanted into the adult rat retina myelinate retinal ganglion cell axons around the point of injection. Inflammation (characterized by increased expression of the macrophage marker ED1 and the astrocyte marker GFAP, and the up-regulation of multiple cytokines) was induced in the retina by the administration of the TLR-2 ligand zymosan. Myelination, revealed by MBP+ myelin sheaths, was substantially increased when OPCs were injected into the inflamed retina compared to that achieved following transplantation into the normal, noninflamed retina. Our results have important implications for the development of immunomodulatory treatments for acute demyelinating disease and for the therapeutic creation of proremyelination environments in chronic demyelinating disease.

Minocycline-mediated inhibition of microglia activation impairs oligodendrocyte progenitor cell responses and remyelination in a non-immune model of demyelination.

Minocycline, a tetracycline derivative, disrupts inflammatory processes within the CNS and reduces demyelination in experimental autoimmune encephalomyelitis. Several recent studies indicate that components of the inflammatory response to demyelination may be beneficial for the regenerative process of remyelination. In this study we examined the effects of minocycline on remyelination independent of its effects in limiting immune-mediated white matter damage using a toxin model of demyelination. Demyelinating lesions were induced by injection of ethidium bromide into caudal cerebellar peduncles of adult rats. Minocycline or PBS was administered by twice daily injections from day 1 prior to lesion-induction to post lesion day 3. Remyelination was assessed, blinded to grouping, using standard morphological criteria. The microglia activation within the lesion was assessed by examining the expression of OX-42 and major histocompatibility class II immunoreactivity. The oligodendrocyte progenitor cell (OPC) response was quantified by in situ hybridization using probes for OPC-expressed mRNAs, platelet-derived growth factor receptor-alpha and Olig-1. Minocycline treatment strongly inhibited microglia/macrophage activation at day 1 and day 3 post-lesion induction, and suppressed the OPC response to demyelination. We also found a significant decrease in the extent of oligodendrocyte but not Schwann cell remyelination in the minocycline-treated animals as compared with controls at 3 weeks post-lesion induction. These results indicate that microglia/macrophage activation is an important process for remyelination and further support the concept that suppression of inflammatory response may impair remyelination.

CNS axons retain their competence for myelination throughout life.

An important question relevant to developing remyelination therapies is whether axons that remain without myelin sheaths after an episode of demyelination retain myelination competence. To resolve this, we have developed a model of transplantation into the nerve fibre layer of the adult rat retina, where the axons are unmyelinated. In the adult, these axons can be myelinated by transplantation of both the oligodendrocyte progenitor cells (OPCs) and an OPC line (CG4). The extent of myelination achieved following transplantation of OPCs is the same in young adult recipients (2 months old) as that which occurs in old adult recipients (12-18 months old), indicating that there are no changes in axons remaining unmyelinated for many months that would prevent effective remyelination. This finding suggests that chronically demyelinated regions of axons such as those in seen in multiple sclerosis are likely to remain competent to be remyelinated.