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

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...

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Main Authors:	Stoffels, Josephine M. J., Hoekstra, Dick, Franklin, Robin J. M., Baron, Wia, Zhao, Chao
Format:	Online
Language:	English
Published:	John Wiley and Sons Inc. 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737254/

id	pubmed-4737254
recordtype	oai_dc
spelling	pubmed-47372542016-02-11 The EIIIA domain from astrocyte‐derived fibronectin mediates proliferation of oligodendrocyte progenitor cells following CNS demyelination Stoffels, Josephine M. J. Hoekstra, Dick Franklin, Robin J. M. Baron, Wia Zhao, Chao Research Articles 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 John Wiley and Sons Inc. 2014-08-25 2015-02 /pmc/articles/PMC4737254/ /pubmed/25156142 http://dx.doi.org/10.1002/glia.22748 Text en © 2014 The Authors. Glia Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Stoffels, Josephine M. J. Hoekstra, Dick Franklin, Robin J. M. Baron, Wia Zhao, Chao
spellingShingle	Stoffels, Josephine M. J. Hoekstra, Dick Franklin, Robin J. M. Baron, Wia Zhao, Chao The EIIIA domain from astrocyte‐derived fibronectin mediates proliferation of oligodendrocyte progenitor cells following CNS demyelination
author_facet	Stoffels, Josephine M. J. Hoekstra, Dick Franklin, Robin J. M. Baron, Wia Zhao, Chao
author_sort	Stoffels, Josephine M. J.
title	The EIIIA domain from astrocyte‐derived fibronectin mediates proliferation of oligodendrocyte progenitor cells following CNS demyelination
title_short	The EIIIA domain from astrocyte‐derived fibronectin mediates proliferation of oligodendrocyte progenitor cells following CNS demyelination
title_full	The EIIIA domain from astrocyte‐derived fibronectin mediates proliferation of oligodendrocyte progenitor cells following CNS demyelination
title_fullStr	The EIIIA domain from astrocyte‐derived fibronectin mediates proliferation of oligodendrocyte progenitor cells following CNS demyelination
title_full_unstemmed	The EIIIA domain from astrocyte‐derived fibronectin mediates proliferation of oligodendrocyte progenitor cells following CNS demyelination
title_sort	eiiia domain from astrocyte‐derived fibronectin mediates proliferation of oligodendrocyte progenitor cells following cns demyelination
description	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
publisher	John Wiley and Sons Inc.
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737254/
_version_	1613532345558630400

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

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