Fibronectin aggregation in multiple sclerosis lesions impairs remyelination

Abstract

Remyelination following central nervous system demyelination is essential to prevent axon degeneration. However, remyelination ultimately fails in demyelinating diseases such as multiple sclerosis. This failure of remyelination is likely mediated by many factors, including changes in the extracellular signalling environment. Here, we examined the expression of the extracellular matrix molecule fibronectin on demyelinating injury and how this affects remyelination by oligodendrocytes progenitors. In toxin-induced lesions undergoing efficient remyelination, fibronectin expression was transiently increased within demyelinated areas and declined as remyelination proceeded. Fibronectin levels increased both by leakage from the blood circulation and by production from central nervous system resident cells. In chronically demyelinated multiple sclerosis lesions, fibronectin expression persisted in the form of aggregates, which may render fibronectin resistant to degradation. Aggregation of fibronectin was similarly observed at the relapse phase of chronic experimental autoimmune encephalitis, but not on toxin-induced demyelination, suggesting that fibronectin aggregation is mediated by inflammation-induced demyelination. Indeed, the inflammatory mediator lipopolysaccharide induced fibronectin aggregation by astrocytes. Most intriguingly, injection of astrocyte-derived fibronectin aggregates in toxin-induced demyelinated lesions inhibited oligodendrocyte differentiation and remyelination, and fibronectin aggregates are barely expressed in remyelinated multiple sclerosis lesions. Therefore, these findings suggest that fibronectin aggregates within multiple sclerosis lesions contribute to remyelination failure. Hence, the inhibitory signals induced by fibronectin aggregates or factors that affect fibronectin aggregation could be potential therapeutic targets for promoting remyelination.

Pathophysiology of the brain extracellular matrix: a new target for remyelination

“…Moreover, compared with wild-type animals, mice lacking this protein had increased numbers of dying oligodendrocyte precursor cells (OPCs) in the subventricular zone at birth and showed delayed maturation of oligodendrocytes in the corpus callosum 38 . In contrast to permissive laminins, fibronectin impedes the morphological differentiation of oligodendrocytes 39 as well as remyelination 40 . Tenascin C and collagen inhibit the migration of OPCs, whereas tenascin R induces their differentiation 41 .…”

Exploring potential mechanisms of action of natalizumab in secondary progressive multiple sclerosis

“…Fibronectin is expressed in chronically demyelinated MS lesions [van Horssen et al 2006], where it appears to accumulate [Stoffels et al 2013]. Natalizumab treatment in patients with RRMS significantly reduced the adhesion of ex vivo peripheral blood mononuclear cells to activated transfected human brain microvascular endothelial cells (THBMECs) under flow conditions; fibronectin containing the CS1 region was identified as the ligand of α4-integrin on the THBMECs [Man et al 2009].…”

Role of autophagy in the pathogenesis of multiple sclerosis

“…The extracellular matrix molecule fibronectin aggregates in chronically demyelinating MS and the relapsig phase of EAE; it may be resistant to degradation and affect the remyelination process [18] .…”