Remyelination is the generation of new myelin sheaths after injury facilitated by processes of differentiating oligodendrocyte precursor cells (OPCs). Although this repair phenomenon occurs in lesions of multiple sclerosis patients, many lesions fail to completely remyelinate. A number of factors have been identified that contribute to remyelination failure, including the upregulated chondroitin sulfate proteoglycans (CSPGs) that comprise part of the astrogliotic scar. We show that in vitro, OPCs have dramatically reduced process outgrowth in the presence of CSPGs, and a medication library that includes a number of recently reported OPC differentiation drugs failed to rescue this inhibitory phenotype on CSPGs. We introduce a novel CSPG synthesis inhibitor to reduce CSPG content and find rescued process outgrowth from OPCs in vitro and accelerated remyelination following focal demyelination in mice. Preventing CSPG deposition into the lesion microenvironment may be a useful strategy to promote repair in multiple sclerosis and other neurological disorders.

MRI and histological studies have shown global alterations in iron levels in the brains of patients with multiple sclerosis (MS), including increases in the iron stored by macrophages and microglia. Excessive free iron can be toxic, and accumulation of iron in MS has generally been thought to be detrimental. However, iron maintains the integrity of oligodendrocytes and myelin, and facilitates their regeneration following injury. The extracellular matrix, a key regulator of remyelination, might also modulate iron levels. This Review highlights key histological and MRI studies that have investigated changes in iron distribution associated with MS. Potential sources of iron, as well as iron regulatory proteins and the detrimental roles of excessive iron within the CNS, are also discussed, with emphasis on the importance of iron within cells for oxidative metabolism, proliferation and differentiation of oligodendrocytes, and myelination. In light of the beneficial and detrimental properties of iron within the CNS, we present considerations for treatments that target iron in MS. Such treatments must balance trophic and toxic properties of iron, by providing sufficient iron levels for remyelination and repair while avoiding excesses that might overwhelm homeostatic mechanisms and contribute to damage.

Multiple sclerosis presents with profound changes in the network of molecules involved in maintaining central nervous system architecture, the extracellular matrix. The extracellular matrix components, particularly the chondroitin sulfate proteoglycans, have functions beyond structural support including their potential interaction with, and regulation of, inflammatory molecules. To investigate the roles of chondroitin sulfate proteoglycans in multiple sclerosis, we used the experimental autoimmune encephalomyelitis model in a time course study. We found that the 4-sulfated glycosaminoglycan side chains of chondroitin sulfate proteoglycans, and the core protein of a particular family member, versican V1, were upregulated in the spinal cord of mice at peak clinical severity, correspondent with areas of inflammation. Versican V1 expression in the spinal cord rose progressively over the course of experimental autoimmune encephalomyelitis. A particular structure in the spinal cord and cerebellum that presented with intense upregulation of chondroitin sulfate proteoglycans is the leucocyte-containing perivascular cuff, an important portal of entry of immune cells into the central nervous system parenchyma. In these inflammatory perivascular cuffs, versican V1 and the glycosaminoglycan side chains of chondroitin sulfate proteoglycans were observed by immunohistochemistry within and in proximity to lymphocytes and macrophages as they migrated across the basement membrane into the central nervous system. Expression of versican V1 transcript was also documented in infiltrating CD45+ leucocytes and F4/80+ macrophages by in situ hybridization. To test the hypothesis that the chondroitin sulfate proteoglycans regulate leucocyte mobility, we used macrophages in tissue culture studies. Chondroitin sulfate proteoglycans significantly upregulated pro-inflammatory cytokines and chemokines in macrophages. Strikingly, and more potently than the toll-like receptor-4 ligand lipopolysaccharide, chondroitin sulfate proteoglycans increased the levels of several members of the matrix metalloproteinase family, which are implicated in the capacity of leucocytes to cross barriers. In support, the migratory capacity of macrophages in vitro in a Boyden chamber transwell assay was enhanced by chondroitin sulfate proteoglycans. Finally, using brain specimens from four subjects with multiple sclerosis with active lesions, we found chondroitin sulfate proteoglycans to be associated with leucocytes in inflammatory perivascular cuffs in all four patients. We conclude that the accumulation of chondroitin sulfate proteoglycans in the perivascular cuff in multiple sclerosis and experimental autoimmune encephalomyelitis boosts the activity and migration of leucocytes across the glia limitans into the central nervous system parenchyma. Thus, chondroitin sulfate proteoglycans represent a new class of molecules to overcome in order to reduce the inflammatory cascades and clinical severity of multiple sclerosis.

The repair of myelin, termed remyelination, is a regenerative process that occurs within the central nervous system in conditions such as multiple sclerosis. Remyelination is enabled by oligodendrocytes that mature from oligodendrocyte precursor cells. Many factors influence the biology of oligodendrocytes and their capacity to reform myelin, and considerable evidence now implicates the extracellular matrix within the injured central nervous system as a major modifier of remyelination. Herein, we review current knowledge of components of the brain extracellular matrix that are beneficial or inhibitory for oligodendrocyte recruitment and maturation, and for their capacity to remyelinate where evidence exists. We highlight the detrimental roles of the chondroitin sulfate proteoglycans in remyelination and discuss approaches to alter the brain extracellular matrix for the wellbeing of oligodendrocytes and their capacity for myelin regeneration.

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