Grey matter OPCs are less mature and less sensitive to IFN\u03b3 than white matter OPCs: consequences for remyelination

Dennis H Lentferink,Inge Werkman,Jacomien M Jongsma,Wia Baron

doi:10.1038/s41598-018-19934-6

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease characterized by the formation of demyelinated lesions in the central nervous system. At later stages of the disease repair in the form of remyelination often fails, which leads to axonal degeneration and neurological disability. For the regeneration of myelin, oligodendrocyte progenitor cells (OPCs) have to migrate, proliferate and differentiate into remyelinating oligodendrocytes. Remyelination occurs faster and is more extensive in grey matter (GM) lesions than in white matter (WM) lesions. Here, we examined differences in neonatal OPCs from GM (gmOPCs) and WM (wmOPCs), both intrinsically and in response to environmental (injury) signals. We show that gmOPCs are less mature than wmOPCs, both on morphological and on gene-expression level. Additionally, gmOPCs proliferate more and differentiate slower than wmOPCs. When exposed to astrocyte-secreted signals wmOPC, but not gmOPC, migration decreases. In addition, wmOPCs are more sensitive to the detrimental effects of IFNγ treatment on proliferation, differentiation, and process arborisation, which is potentiated by TNFα. Our results demonstrate that OPCs from GM and WM differ both intrinsically and in response to their environment, which may contribute to the difference in remyelination efficiency between GM and WM MS lesions.

Highlights

Multiple sclerosis (MS) is a chronic inflammatory disease in which demyelinated lesions are present both in the grey (GM) and white matter (WM) of the central nervous system
We assessed whether regional oligodendrocyte progenitor cells (OPCs) differentially respond to environmental signals that are present in healthy tissue, such as factors secreted by astrocytes, and in demyelinated (MS) lesions, such as the pro-inflammatory cytokines tumour necrosis factor-α (TNFα) and interferon-γ (IFNγ)[24]
To examine the effect of pro-inflammatory cytokines on cell behaviour aspects that are relevant to OPC recruitment, we examined the effect of TNFα and IFNγ on gmOPC and wmOPC migration and proliferation compared to their respective untreated control OPCs

Summary

Introduction

Multiple sclerosis (MS) is a chronic inflammatory disease in which demyelinated lesions are present both in the grey (GM) and white matter (WM) of the central nervous system. In MS lesions[7,9,10] and upon toxin-induced demyelination[11], remyelination is more efficient in the GM than in the WM This may at least partially be due to a higher OPC density in GM lesions[7], and micro-environmental factors influencing OPC differentiation like spatial differences in inflammatory signals[12,13,14,15,16], extracellular matrix composition[7] and differences in the spatial and temporal expression of growth factors[17]. Our findings revealed that gmOPCs are less mature and wmOPCs are more susceptible to IFNγ-mediated inhibition of OPC proliferation, differentiation and process arborisation. These intrinsic and functional differences may contribute to the observed increased remyelination efficiency of demyelinated GM lesions compared to WM lesions in physiological and pathological conditions, i.e., MS

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