Dynamic interplay between the ageing CNS progenitor cells and their surrounding niche (360G-Wellcome-109139_Z_15_A)

The pathological loss of myelin sheath from axons predisposes neurons to atrophy and subsequent death. In response to brain demyelination, a cell population called oligodendrocyte progenitor cells (OPCs) proliferate and differentiate into oligodendrocytes (OLs), which remyelinate exposed axons. In ageing remyelination often fails due to a reduction in OPC regenerative capacity. The age-related reduction in remyelination coincides with changes in the brain biochemical and mechanical properties. Preliminary data have demonstrated that exposure of aged OPCs to young-like environments improves aged OPC function in terms of proliferation and differentiation into myelinating OLs. This project aims to identify factors from the physical extracellular microenvironment, which negatively influence remyelination in the ageing CNS. In order to elucidate the underlying molecular mechanisms, the composition of the brain tissue changes with age on a biochemical and mechanical level and and its influence on the OPC proliferation and differentiation into OLs will be investigated. Moreover, the negative effects of the ageing microenvironment will be mitigated by mimicking the young brain niche using synthetic scaffolds as well as modified decellularised tissue. Understanding this interplay using a range of in vitro and in vivo methods will therefore aid the development of therapies for enhancing endogenous remyelination.