Insufficient OPC migration into demyelinated lesions is a cause of poor remyelination in MS and mouse models

Amanda Boyd,Hui Zhang,Anna Williams

doi:10.1007/s00401-013-1112-y

Amanda Boyd, Hui Zhang + Show 1 more

Open Access

https://doi.org/10.1007/s00401-013-1112-y

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Abstract

Failure of remyelination of multiple sclerosis (MS) lesions contributes to neurodegeneration that correlates with chronic disability in patients. Currently, there are no available treatments to reduce neurodegeneration, but one therapeutic approach to fill this unmet need is to promote remyelination. As many demyelinated MS lesions contain plentiful oligodendrocyte precursor cells (OPCs), but no mature myelinating oligodendrocytes, research has previously concentrated on promoting OPC maturation. However, some MS lesions contain few OPCs, and therefore, remyelination failure may also be secondary to OPC recruitment failure. Here, in a series of MS samples, we determined how many lesions contained few OPCs, and correlated this to pathological subtype and expression of the chemotactic molecules Semaphorin (Sema) 3A and 3F. 37 % of MS lesions contained low numbers of OPCs, and these were mostly chronic active lesions, in which cells expressed Sema3A (chemorepellent). To test the hypothesis that differential Sema3 expression in demyelinated lesions alters OPC recruitment and the efficiency of subsequent remyelination, we used a focal myelinotoxic mouse model of demyelination. Adding recombinant (r)Sema3A (chemorepellent) to demyelinated lesions reduced OPC recruitment and remyelination, whereas the addition of rSema3F (chemoattractant), or use of transgenic mice with reduced Sema3A expression increased OPC recruitment and remyelination. We conclude that some MS lesions fail to remyelinate secondary to reduced OPC recruitment, and that chemotactic molecules are involved in the mechanism, providing a new group of drug targets to improve remyelination, with a specific target in the Sema3A receptor neuropilin-1.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1112-y) contains supplementary material, which is available to authorized users.

Highlights

The quest for discovery of molecules that improve CNS remyelination is prompted by the premise that this will help repair demyelinated lesions in multiple sclerosis (MS), aiding symptoms by overcoming conduction block and temporal dispersion of action potentials by restoring saltatory conduction, and protect axons from neurodegeneration which causes progressive disability [8, 24]
Many papers state that the cause of remyelination failure in MS is due to arrest of oligodendroglial maturation within a demyelinated plaque, as most MS lesions contain sufficient oligodendrocyte precursor cells (OPCs)
We have shown that the number of OPCs present in MS lesions in postmortem brain is highly variable, both within lesions and between lesions

Summary

Introduction

The quest for discovery of molecules that improve CNS remyelination is prompted by the premise that this will help repair demyelinated lesions in multiple sclerosis (MS), aiding symptoms by overcoming conduction block and temporal dispersion of action potentials by restoring saltatory conduction, and protect axons from neurodegeneration which causes progressive disability [8, 24]. Oligodendrocyte precursor cells (OPCs) must survive, proliferate, migrate to the lesion and differentiate into mature oligodendrocytes forming compact myelin sheaths [12]. Failure of remyelination may occur at any step in this process, but it is thought to be mostly due to failure or arrest of oligodendroglial differentiation. This is partly due to pathological studies revealing that 60–70 % of demyelinated MS lesions contain oligodendroglial cells in an arrested maturation state [6, 27] and is reflected in the molecules associated with altering CNS remyelination in rodents, which all promote oligodendroglial maturation: 9-cis retinoic acid [17], anti-Lingo-1 antibodies

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