Macroglial diversity and its effect on myelination

Abstract

Multiple sclerosis (MS) is a chronic disease of the central nervous system characterized by local loss of myelin, a protective, isolating layer around axons. Myelin can be restored by a natural regenerative process, called remyelination. However, remyelination ultimately fails in MS. Successful remyelination requires the maturation of oligodendrocyte progenitor cells (OPCs) into myelin forming oligodendrocytes. Remyelination is orchestrated by astrocytes. Notably, remyelination is more efficient in grey compared to white matter. In this thesis we investigated whether astrocytes from grey and white matter distinctly modulate OPC functioning and maturation. We demonstrate that astrocytes and OPCs from grey matter may together provide an environment that is more effective in the regeneration of myelin than astrocytes and OPCs from white matter. White matter astrocytes supported myelin formation less than grey matter astrocytes, partially due to producing more inhibitory fibronectin aggregates. In addition, grey matter OPCs appeared better equipped for remyelination. Unexpectedly, specific inhibition of cholesterol biosynthesis in white matter astrocytes enhanced myelin formation by oligodendrocytes. This finding provides a possible new target for promoting myelin formation in white matter. Taken together, research into the failure of remyelination in MS will benefit from taking into account regional differences between cells from grey and white matter. This awareness will contribute to an improved insight into the disease progression of MS. In addition, this will provide challenging opportunities for the development of more specific and thereby efficiency increasing therapy for the treatment of MS, directed at improving myelin recovery in MS lesions.