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Stoffels, Josephine M. J., de Jonge, Jenny C., Stancic, Mirjana, Nomden, Anita, van Strien, Miriam E., Ma, Dan, Šišková, Zuzana, Maier, Olaf, ffrench-Constant, Charles 
ORCID: https://orcid.org/0000-0002-5621-3377, Franklin, Robin J. M., Hoekstra, Dick, Zhao, Chao and Baron, Wia
(2013)
Fibronectin aggregation in multiple sclerosis lesions impairs remyelination.
Brain, 136 (1).
pp. 116-131.
ISSN 0006-8950
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.
| Item Type: | Article |
|---|---|
| Additional Information: | Funding Information: This work was supported by grants from the Dutch MS Research Foundation (‘Stichting MS Research’, W.B., J.M.J.S.), the UK MS Society (C.Z., R.J.M.F.), the Netherlands Organization of Scientific Research [NWO, W.B. (VIDI and Aspasia), Z.S.], Prinses Beatrix Fonds (J.M.J.S.), Marco Polo Fonds (J.M.J.S.), J.K. de Cock Stichting (J.M.J.S.), and Groninger Universiteits Fonds (J.M.J.S.). |
| Uncontrolled Keywords: | astrocyte,fibronectin,multiple sclerosis,oligodendrocyte,remyelination,clinical neurology ,/dk/atira/pure/subjectarea/asjc/2700/2728 |
| Faculty \ School: | Faculty of Medicine and Health Sciences > Norwich Medical School |
| Related URLs: | |
| Depositing User: | LivePure Connector |
| Date Deposited: | 16 Jul 2022 00:27 |
| Last Modified: | 22 Oct 2022 18:37 |
| URI: | https://ueaeprints.uea.ac.uk/id/eprint/86277 |
| DOI: | 10.1093/brain/aws313 |
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