Central nervous system remyelination in culture — A tool for multiple sclerosis research

Hui Zhang,Andrew A Jarjour,Amanda Boyd,Anna Williams

doi:10.1016/j.expneurol.2011.04.009

Abstract

Multiple sclerosis is a demyelinating disease of the central nervous system which only affects humans. This makes it difficult to study at a molecular level, and to develop and test potential therapies that may change the course of the disease. The development of therapies to promote remyelination in multiple sclerosis is a key research aim, to both aid restoration of electrical impulse conduction in nerves and provide neuroprotection, reducing disability in patients.Testing a remyelination therapy in the many and various in vivo models of multiple sclerosis is expensive in terms of time, animals and money. We report the development and characterisation of an ex vivo slice culture system using mouse brain and spinal cord, allowing investigation of myelination, demyelination and remyelination, which can be used as an initial reliable screen to select the most promising remyelination strategies. We have automated the quantification of myelin to provide a high content and moderately-high-throughput screen for testing therapies for remyelination both by endogenous and exogenous means and as an invaluable way of studying the biology of remyelination.

Highlights

Multiple sclerosis (MS) is the commonest cause of disability in young people in the western world after trauma, with Scotland having the highest prevalence of patients in the world (1 in 500 people)
Using antibodies against the marker of proliferation PCNA, we showed that treatment with LPC causing demyelination provoked a proliferative response, which subsided with remyelination
Addition of various factors to in vitro co-culture models of developmental myelination have been shown to alter myelination. Several of these factors fail to affect remyelination in in vivo models. We tested these known factors in our cerebellar slice model for their influence on remyelination, in order to test the fidelity of our slice system to the in vivo situation

Summary

Introduction

Multiple sclerosis (MS) is the commonest cause of disability in young people in the western world after trauma, with Scotland having the highest prevalence of patients in the world (1 in 500 people). The cause of MS is not clear, but its pathology consists of immune infiltration into the central nervous system (CNS), inflammation, demyelination and axonal degeneration (Dubois-Dalcq et al, 2008). The presence of demyelinating plaques in the CNS corresponds to MS relapses, but it is axonal degeneration which correlates with progressive disability (De Stefano et al, 2001; Fisniku et al, 2008). Myelination of axons allows fast saltatory conduction of electrical impulses, and provides support both mechanically and functionally by cellular communication between the axon and the oligodendrocyte which produces the myelin sheath. Demyelination of axons reduces the conduction velocity of nerve impulses, and makes the axons vulnerable to degeneration (Franklin and Ffrench-Constant, 2008). In MS, some demyelinated plaques contain axons which have been remyelinated, which restores nerve conduction (Duncan et al, 2009; Smith et al, 1981) and protects the nerve from subsequent degeneration (Irvine and Blakemore, 2008).

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