Abstract
Central nervous system remyelination by oligodendrocyte progenitor cells (OPCs) ultimately fails in the majority of multiple sclerosis (MS) lesions. Remyelination benefits from transient expression of factors that promote migration and proliferation of OPCs, which may include fibronectin (Fn). Fn is present in demyelinated lesions in two major forms; plasma Fn (pFn), deposited following blood‐brain barrier disruption, and cellular Fn, synthesized by resident glial cells and containing alternatively spliced domains EIIIA and EIIIB. Here, we investigated the distinctive roles that astrocyte‐derived Fn (aFn) and pFn play in remyelination. We used an inducible Cre‐lox recombination strategy to selectively remove pFn, aFn or both from mice, and examined the impact on remyelination of toxin‐induced demyelinated lesions of spinal cord white matter. This approach revealed that astrocytes are a major source of Fn in demyelinated lesions. Furthermore, following aFn conditional knockout, the number of OPCs recruited to the demyelinated lesion decreased significantly, whereas OPC numbers were unaltered following pFn conditional knockout. However, remyelination completed normally following conditional knockout of aFn and pFn. Both the EIIIA and EIIIB domains of aFn were expressed following demyelination, and in vitro assays demonstrated that the EIIIA domain of aFn mediates proliferation of OPCs, but not migration. Therefore, although the EIIIA domain from aFn mediates OPC proliferation, aFn is not essential for successful remyelination. Since previous findings indicated that astrocyte‐derived Fn aggregates in chronic MS lesions inhibit remyelination, aFn removal may benefit therapeutic strategies to promote remyelination in MS. GLIA 2015;63:242–256
Highlights
Multiple sclerosis (MS) is a central nervous system (CNS) disease, of which inflammation, demyelination, and axonal loss are the main pathological features
Spontaneous and complete remyelination of these lesions proceeds over a period of 21–28 days in young adult rodents, which involves proliferation and migration of local, activated oligodendrocyte progenitor cells (OPCs) to the demyelinated lesions [“recruitment”; 1–10 days post lesion (DPL)], followed by differentiation of oligodendrocytes and myelin sheath formation (10–21 DPL) (Zhao et al, 2006)
During remyelination (14 DPL), mRNA levels of EIIIA, EIIIB, and total Fn returned to lower levels (Fig. 5A–C; 14 DPL). Because both EIIIA and EIIIB mRNA levels are increased at 5-days post lysolecithin-demyelinated lesions (5 DPL), when OPCs are recruited, and since these elements are exclusively present in Fn derived from local cellular sources, such as astrocytes, we examined the extent to which astrocyte-derived Fn (aFn) EIIIA, FIGURE 2: OPC numbers in lysolecithin-induced demyelinated lesions decrease after conditional knockout of astrocyte fibronectin, but not after plasma fibronectin conditional knockout alone
Summary
Multiple sclerosis (MS) is a central nervous system (CNS) disease, of which inflammation, demyelination, and axonal loss are the main pathological features. Regeneration of myelin (remyelination) involves proliferation and migration of activated oligodendrocyte progenitor cells (OPCs) to demyelinated lesions, and their subsequent differentiation into myelinating oligodendrocytes (Franklin and ffrenchConstant, 2008; Zawadzka et al, 2010). The extent of remyelination in MS is variable, but often is insufficient to prevent chronic axonal loss (Franklin et al, 2012; Patrikios et al, 2006). Promoting endogenous remyelination provides a means to reduce axonal degeneration and thereby slow progression of clinical disability (Duncan et al, 2009; Franklin et al, 2012). Fn is absent from the healthy CNS, but expressed following injury, which
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