Inhibitory milieu at the multiple sclerosis lesion site and the challenges for remyelination

Abstract

Regeneration of myelin, following injury, can occur within the central nervous system to reinstate proper axonal conductance and provide trophic support. Failure to do so renders the axons vulnerable, leading to eventual degeneration, and neuronal loss. Thus, it is essential to understand the mechanisms by which remyelination or failure to remyelinate occur, particularly in the context of demyelinating and neurodegenerative disorders. In multiple sclerosis, oligodendrocyte progenitor cells (OPCs) migrate to lesion sites to repair myelin. However, during disease progression, the ability of OPCs to participate in remyelination diminishes coincident with worsening of the symptoms. Remyelination is affected by a broad range of cues from intrinsic programming of OPCs and extrinsic local factors to the immune system and other systemic elements including diet and exercise. Here we review the literature on these diverse inhibitory factors and the challenges they pose to remyelination. Results spanning several disciplines from fundamental preclinical studies to knowledge gained in the clinic will be discussed.

Lesion stage-dependent causes for impaired remyelination in MS

“…In animal experiments, proliferation and migration of oligodendrocyte precursor cells (OPC) as well as their differentiation into mature myelinating oligodendrocytes is required for successful remyelination. These complex processes are regulated by the interaction of OPC and oligodendrocytes with neurons and axons, astrocytes as well as immune cells, such as macrophages/microglia, T cells, and B cells (for review see [24,25,27,42]). In progressive MS, OPC are still present in MS lesions albeit in reduced numbers and unevenly distributed, whereas mature oligodendrocytes are almost completely lacking [11,39,69].…”

Altered astrocytic function in experimental neuroinflammation and multiple sclerosis

“…On the one hand, it presents as a physical barrier that prevents axonal regeneration and remyelination (Bush et al, 1999; Correale & Farez, 2015; Ponath, Park, & Pitt, 2018; Wang et al, 2011). Indeed, reactive astrocytes rapidly upregulate the expression of chondroitin sulfate proteoglycans (CSPGs), such as neurocan and phosphacan, thus inhibiting neurite outgrowth and axonal regeneration (Figure 2; Anderson et al, 2016; Asher et al, 2000; Brosnan & Raine, 2013; Galloway, Gowing, Setayeshgar, & Kothary, 2020; McKeon, Jurynec, & Buck, 1999; Nair, Frederick, & Miller, 2008; Tang, Davies, & Davies, 2003; Wiese, Karus, & Faissner, 2012). On the other hand, in the context of spinal cord injury, one study has observed that astrocytes present in lesion regions express multiple axon‐growth supporting molecules, which could indicate that the glial scar can also aid in CNS axonal regeneration (Anderson et al, 2016).…”

Multiple Sclerosis: Melatonin, Orexin, and Ceramide Interact with Platelet Activation Coagulation Factors and Gut-Microbiome-Derived Butyrate in the Circadian Dysregulation of Mitochondria in Glia and Immune Cells

“…This suggests that the suppression of OPC differentiation and increased BBB permeability may be coordinated by astrocytes. A number of other factors act to inhibit remyelination, including immune, miRNAs, and aging [37], with the mitochondrial optimizing effects of creatine increasing oligodendrocyte survival and OPC differentiation [38]. Such data highlight the importance of gut microbiome-derived butyrate, via optimized mitochondrial function, for the regulation of classical MS pathophysiology.…”