title: 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.
authors.affiliation: Department of Cell Biology, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Josephine M J
authors.initials: JM
authors.lastname: Stoffels
authors.forename: Dick
authors.initials: D
authors.lastname: Hoekstra
authors.forename: Robin J M
authors.initials: RJ
authors.lastname: Franklin
authors.forename: Wia
authors.initials: W
authors.lastname: Baron
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002448:Cell Adhesion / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000473:pathology*; D004195:Disease Models, Animal; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D009416:Nerve Regeneration / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D000076104:Oligodendrocyte Transcription Factor 2; D009836:Oligodendroglia / Q000502:physiology*; D055748:SOXB1 Transcription Factors / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology*; D013234:Stem Cells / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D029961:Zebrafish Proteins
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005353:Fibronectins; D005904:Glial Fibrillary Acidic Protein; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D019394:Ki-67 Antigen; D008244:Lysophosphatidylcholines; D009419:Nerve Tissue Proteins; D000076104:Oligodendrocyte Transcription Factor 2; D055748:SOXB1 Transcription Factors; D014157:Transcription Factors; D029961:Zebrafish Proteins; C512773:Olig2 protein, mouse; C527783:Sox2 protein, mouse; C572454:extra domain A fibronectin, mouse
keywords: astrocyte; fibronectin; multiple sclerosis; oligodendrocyte; remyelination