Fibronectin aggregation in multiple sclerosis lesions impairs remyelination

被引:149
作者
Stoffels, Josephine M. J. [1 ]
de Jonge, Jenny C. [1 ]
Stancic, Mirjana [1 ]
Nomden, Anita [1 ]
van Strien, Miriam E. [2 ]
Ma, Dan [3 ,4 ]
Siskova, Zuzana [1 ]
Maier, Olaf [1 ]
Ffrench-Constant, Charles [5 ]
Franklin, Robin J. M. [3 ,4 ]
Hoekstra, Dick [1 ]
Zhao, Chao [3 ,4 ]
Baron, Wia [1 ]
机构
[1] Univ Groningen, Univ Med Ctr Groningen, Dept Cell Biol, NL-9713 AB Groningen, Netherlands
[2] Vrije Univ Amsterdam, Dept Anat & Neurosci, Med Ctr, NL-1007 MB Amsterdam, Netherlands
[3] Univ Cambridge, Wellcome Trust, MRC, Stem Cell Inst, Cambridge CB3 0ES, England
[4] Univ Cambridge, Dept Vet Med, Cambridge CB3 0ES, England
[5] Ctr Multiple Sclerosis Res, MRC Ctr Regenerat Med, Edinburgh EH16 4UU, Midlothian, Scotland
关键词
fibronectin; multiple sclerosis; remyelination; astrocyte; oligodendrocyte; CENTRAL-NERVOUS-SYSTEM; TOXIN-INDUCED DEMYELINATION; MYELIN MEMBRANE FORMATION; TOLL-LIKE RECEPTORS; EXTRACELLULAR-MATRIX; INCREASED EXPRESSION; EXPERIMENTAL-MODELS; CNS DEMYELINATION; RAFT-ASSOCIATION; PROGENITOR CELLS;
D O I
10.1093/brain/aws313
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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.
引用
收藏
页码:116 / 131
页数:16
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