Abstract
It is now well‐established that the macrophage and microglial response to CNS demyelination influences remyelination by removing myelin debris and secreting a variety of signaling molecules that influence the behaviour of oligodendrocyte progenitor cells (OPCs). Previous studies have shown that changes in microglia contribute to the age‐related decline in the efficiency of remyelination. In this study, we show that microglia increase their expression of the proteoglycan NG2 with age, and that this is associated with an altered micro‐niche generated by aged, but not young, microglia that can divert the differentiation OPCs from oligodendrocytes into astrocytes in vitro. We further show that these changes in ageing microglia are generated by exposure to high levels of TGFβ. Thus, our findings suggest that the rising levels of circulating TGFβ known to occur with ageing contribute to the age‐related decline in remyelination by impairing the ability of microglia to promote oligodendrocyte differentiation from OPCs, and therefore could be a potential therapeutic target to promote remyelination.
Highlights
Remyelination is an important regenerative process in the CNS in which new myelin sheaths are restored to demyelinated axons by oligodendrocytes which are newly generated by adult oligodendrocyte progenitor cells (OPCs) (Franklin and ffrench-Constant, 2017)
We show that extracellular matrix (ECM) deposited by TGFβ treated and aged microglia can directly alter the fate choice of OPCs, directing them toward an astrocytic fate
The effect of ECM and cell to cell contact on OPCs has been shown in relation to other cell types
Summary
Remyelination is an important regenerative process in the CNS in which new myelin sheaths are restored to demyelinated axons by oligodendrocytes which are newly generated by adult oligodendrocyte progenitor cells (OPCs) (Franklin and ffrench-Constant, 2017). This results in the restoration of saltatory conduction, which is lost during demyelination, and protection from irreversible axonal atrophy (Irvine & Blakemore, 2008; Smith, Blakemore, & Mcdonald, 1979). Since TGFβ levels increase with ageing and have been shown to negatively affect hippocampal neurogenesis in the CNS (Buckwalter et al, 2006; Carlson et al, 2009; Doyle, Cekanaviciute, Mamer, & Buckwalter, 2010), we hypothesized that TGFβ-mediated effects on the microglial micro-niche might contribute to the age-related decline in the efficiency of remyelination (Cantuti-Castelvetri et al, 2018; Miron et al, 2013; Ruckh et al, 2012; Shields, Gilson, Blakemore, & Franklin, 1999; Sim, Zhao, Penderis, & Franklin, 2002)
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