The EIIIA domain from astrocyte‐derived fibronectin mediates proliferation of oligodendrocyte progenitor cells following CNS demyelination

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

Extracellular cues influencing oligodendrocyte differentiation and (re)myelination

“…The apparent redundancy of plasma fibronectin, despite its well-documented ability to promote OPC proliferation in vitro , was accounted for by the limited blood-brain barrier break-down in the employed model. Importantly, the deletion of both plasma and astrocyte Fn did not affect the overall extent of OLG differentiation and remyelination (Stoffels et al, 2015), an observation that is consistent with the notion that recruitment of OPCs may not always be the rate-determining factor for remyelination (Franklin and Goldman, 2015). …”

“…Upon CNS injury, two forms of fibronectin, which differ in cellular source and the presence/absence of alternatively spliced domains, can be found: plasma fibronectin leaking through a damaged blood-brain-barrier and cellular fibronectin released by predominantly astrocytes (Stoffels et al, 2013). Genetic ablation of plasma and/or astrocyte fibronectin ( Fn ) in a model of lysolecithin-induced demyelination revealed a role of predominantly astrocyte fibronectin on OPC proliferation, but not migration (Stoffels et al, 2015). The apparent redundancy of plasma fibronectin, despite its well-documented ability to promote OPC proliferation in vitro , was accounted for by the limited blood-brain barrier break-down in the employed model.…”

The extracellular matrix: Focus on oligodendrocyte biology and targeting CSPGs for remyelination therapies

“…Fibronectin aggregates have also been observed in both chronic EAE and chronically demyelinated MS lesions, and injection of astrocyte-derived fibronectin aggregates into experimentally demyelinated lesions resulted in reduced OPC differentiation and remyelination (Stoffels et al, 2013a). In addition, knockout of astrocyte-derived fibronectin resulted in reduced OPC proliferation following demyelination (Stoffels, Hoekstra, Franklin, Baron, & Zhao, 2015). In addition, knockout of astrocyte-derived fibronectin resulted in reduced OPC proliferation following demyelination (Stoffels, Hoekstra, Franklin, Baron, & Zhao, 2015).…”

“…However, Milner et al (Milner et al, 1996) show fibronectin promotes migration of OPCs to a similar extent in vitro compared with laminin. In addition, knockout of astrocyte-derived fibronectin resulted in reduced OPC proliferation following demyelination (Stoffels, Hoekstra, Franklin, Baron, & Zhao, 2015).…”

Heterogeneous astrocytes: Active players in CNS

“…Increasing evidences indicated that astrocytes play critical roles in OPCs and OLs survival, maturity and myelination through the intercellular crosstalk (Fischer et al 2014;Pang et al 2013;Stoffels et al 2015;Su et al 2011). The heterogeneous phenotypes of astrocytes are shown to relevantly affect the myelination capacity.…”