Breaking the barriers to remyelination in multiple sclerosis

Abstract

Chronically demyelinated axons are rendered susceptible to degeneration through loss of trophic support from oligodendrocytes and myelin, and this process underlies disability progression in multiple sclerosis. Promoting remyelination is a promising neuroprotective therapeutic strategy, but to date, has not been achieved through simply promoting oligodendrocyte precursor cell differentiation, and it is clear that a detailed understanding of the molecular mechanisms underlying failed remyelination is required to guide future therapeutic approaches. In multiple sclerosis, remyelination is impaired by extrinsic inhibitory cues in the lesion microenvironment including secreted effector molecules released from compartmentalized immune cells and reactive glia, as well as by intrinsic defects in oligodendrocyte lineage cells, most notably increased metabolic demands causing oxidative stress and accelerated cellular senescence. Promising advances in our understanding of the cellular and molecular mechanisms underlying these processes offers hope for strategically designed interventions to facilitate remyelination thereby resulting in robust clinical benefits.

Figure 1 -. Mechanisms of failed remyelination.

Remyelination is influenced by intrinsic and extrinsic factors that affect OPC proliferation, recruitment, maturation, and myelin sheath extension. Extrinsic factors include pro-inflammatory cytokines and inhibitory cues secreted by immune cells and resident glia, debris from autoimmune attack of the myelin sheath, composition and stiffness of the ECM, and axonal receptivity. Intrinsically, OPC capacity for proliferation and maturation is affected by various surface receptors. In addition, the normal aging process can elicit a senescent phenotype associated with pro-inflammatory secretions, mitochondrial stress, and altered gene expression, culminating in reduced responsiveness to pro-remyelination cues.

Figure 2 -. Targets of clinical remyelination therapies.

Schematic of clinical remyelination strategies targeting intrinsic and extrinsic influences on OPC maturation and survival. OPC, Oligodendrocyte progenitor cells; M1 muscarinic receptors; H1 histamine receptors; RXR, retinoic acid receptor; PPAR, peroxisome proliferator-activated receptor; AMPK, AMP-activated kinase; TR, Thyroid receptor.