Changes in the Oligodendrocyte Progenitor Cell Nuclear Lamina During Ageing

Abstract

Following the loss of oligodendrocytes in demyelinating diseases such as multiple sclerosis (MS), new oligodendrocytes can be generated from the oligodendrocyte progenitor cell (OPC), a multipotent progenitor cell of the central nervous system. However, the efficiency of this regenerative process declines with ageing, leading to neurodegeneration and progressive neurological dysfunction in older individuals with MS. Therefore, understanding the mechanisms of OPC ageing, and how these mechanisms might be slowed or reversed, is imperative in the search for new therapies for demyelinating diseases, with the aim of enhancing remyelination following demyelinating injuries in older individuals. A recently discovered regulator of OPC ageing is the stiffness of the OPC microenvironment, with exposure of aged OPCs to mechanically softer microenvironments enhancing their regenerative properties. However, the mechanisms underlying this phenomenon remain unclear. The purpose of this thesis was to explore a possible role of the nuclear lamina (a nucleoplasmic protein scaffold) in the functional response of OPCs to the mechanical properties of their microenvironment. Work in this thesis identified changes in the expression levels of the nuclear lamina proteins Lamin A/C and Lamin B1, and changes in the subcellular localisation of the nuclear lamina protein emerin, occurring both with ageing and upon exposure to hydrogels of different stiffnesses. Knock-down experiments suggest that this changing localisation of emerin may play a causal role in the changing regenerative potential of OPCs. The potential epigenetic implications of these changes in the OPC nuclear lamina were explored, with changes in the global levels of H3K9me3 and H3K27me3 in OPCs being identified, both with ageing and upon exposure to environments of different stiffnesses. Overall, work in this thesis identifies several novel nuclear and epigenetic changes occurring in OPCs with ageing and in response to mechanical cues. This thesis concludes by considering broader questions which should be addressed in order to gain a more comprehensive understanding of the mechanobiology of OPCs.