Cortical remyelination: A new target for repair therapies in multiple sclerosis

Abstract

Objective Generation and differentiation of new oligodendrocytes in demyelinated white matter is the best described repair process in the adult human brain. However, remyelinating capacity falters with age in patients with multiple sclerosis. (MS). Since demyelination of cerebral cortex is extensive in brains from MS patients, we investigated the capacity of cortical lesions to remyelinate and directly compared the extent of remyelination in lesions that involve cerebral cortex and adjacent subcortical white matter. Methods Postmortem brain tissue from 22 patients with MS (age 27 to 77 years) and 6 subjects without brain disease were analyzed. Regions of cerebral cortex with reduced myelin were examined for remyelination, oligodendrocyte progenitor cells, reactive astrocytes, and molecules that inhibit remyelination. Results “New” oligodendrocytes that were actively forming myelin sheaths were identified in 30/42 remyelinated subpial cortical lesions, including lesions from three patients in their 70's. Oligodendrocyte progenitor cells were not decreased in demyelinated or remyelinated cortices when compared to adjacent normal-appearing cortex or controls. In demyelinated lesions involving cortex and adjacent white matter, the cortex showed greater remyelination, more actively remyelinating oligodendrocytes and fewer reactive astrocytes. Astrocytes in the white-matter, but not in cortical portions of these lesions, significantly up-regulate CD44, hyaluronan, and versican, molecules that form complexes that inhibit oligodendrocyte maturation and remyelination. Interpretation Endogenous remyelination of the cerebral cortex occurs in individuals with MS regardless of disease duration or chronological age of the patient. Cortical remyelination should be considered as a primary outcome measure in future clinical trials testing remyelination therapies.

The Anti-Aging Protein Klotho Enhances Remyelination Following Cuprizone-Induced Demyelination

“…The generation of new OPCs and myelin can be observed in white matter lesions at the early stages of the disease (Prineas et al 1993;Lucchinetti et al 1999;Chang et al 2012), while the majority of chronically demyelinated lesions in white matter demonstrate restricted remyelination due to a reduced recruitment of OPCs, the failure of OPCs to produce mature oligodendrocytes, and the insufficient production of myelin sheath by OLs (Trapp et al 1997;Wolswijk 2000;Chang et al 2002;Kuhlmann et al 2008;Chang et al 2012). Importantly, it was also shown that in the corpus callosum, premyelinating OLs usually occur in groups and their processes overlap extensively, which allows the clusters of OLs to compete more effectively for the survival factors in the neighborhood (Trapp et al 1997).…”

“…Quantification of myelination, OPCs, and OLs were processed as previously described (Dutta et al 2011;Chang et al 2012;Sachs et al 2014). Briefly, free-floating sections (30 μm) of the corpus callosum were stained with antibodies to PLP (Cleveland Clinic Hybridoma), PDGFRα (Cell Signaling), and GSTpi (Assay Designs) to quantify myelin, OPCs, and OLs, respectively.…”

“…The generation of new oligodendrocytes (OLs) and myelin are prominent features of white matter lesions during early stages of MS Prineas et al (1993). The reduced recruitment of oligodendrocyte progenitor cells (OPCs), insufficient generation of OPCs into OLs, and failure of OL differentiation into mature myelin forming cells were shown to be the prominent contributors to chronically demyelinated white matter lesions in MS brains (Chang et al 2000;Chang et al 2002;Kuhlmann et al 2008;Chang et al 2012). Remission is mainly achieved by migration of OPCs to sites of injury and their subsequent maturation into myelin-producing cells, while the inhibition of OPC differentiation at sites of lesion was recognized as a major contributor to disease progression (Trapp et al 1998;Chang et al 2002).…”

A Sativex®‐like combination of phytocannabinoids as a disease‐modifying therapy in a viral model of multiple sclerosis

“…In MS, repair and remyelination occur in shadow plaques (Chang et al, 2012) but, as the disease progresses, remyelination becomes less efficient (Chang et al, 2002;Franklin, 2002;Goldschmidt et al, 2009). It is unlikely that the inability to remyelinate results from the absence of oligodendrocyte precursor cells (OPCs) in the adult CNS, as OPCs are present in elderly patients even decades after having been diagnosed with the disease (Chang et al, 2012). Alternatively, the failure in remyelination might reflect changes in the local extracellular environment, specifically those affecting the extracellular matrix (ECM) proteins and chondroitin sulfate proteoglycans (CSPGs).…”

Is the Relationship between Cortical and White Matter Pathologic Changes in Multiple Sclerosis Spatially Specific? A Multimodal 7-T and 3-T MR Imaging Study with Surface and Tract-based Analysis

“…Another explanation could be that remyelination and repair across several cortical regions and the periventricular portion of the corticospinal tract, which could reflect concomitant pathophysiologic mechanisms normal-appearing WM of MS patients relative to control participants (37). Interestingly, we found an association between intracortical pathologic changes capacities, known to occur both in the cortex and in the WM (38,39), may be exceeded in cortical and WM regions not necessarily spatially connected. Some limitations apply to this study.…”