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

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Stoffels, Josephine MJ 
Hoekstra, Dick 
Franklin, Robin JM 
Baron, Wia 


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.



astrocyte, fibronectin, multiple sclerosis, oligodendrocyte, remyelination, Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Adhesion, Cell Differentiation, Cell Movement, Cell Proliferation, Demyelinating Diseases, Disease Models, Animal, Fibronectins, Glial Fibrillary Acidic Protein, Homeobox Protein Nkx-2.2, Homeodomain Proteins, Humans, Ki-67 Antigen, Lysophosphatidylcholines, Mice, Mice, Knockout, Nerve Regeneration, Nerve Tissue Proteins, Oligodendrocyte Transcription Factor 2, Oligodendroglia, SOXB1 Transcription Factors, Spinal Cord, Stem Cells, Transcription Factors, Zebrafish Proteins

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JMJS is recipient of a Junior Scientific Masterclass MD/PhD fellowship from the University Medical Center Groningen. This work was supported by grants from the Netherlands Organization of Scientific Research (NWO, WB, VIDI and Aspasia), the Dutch MS Research Foundation (‘Stichting MS Research’, WB, JMJS, DH), the UK MS Society (CZ, RJMF), and the Research School of Behavioral and Cognitive Neurosciences (BCN, JMJS). Parts of this study were performed at the UMCG Microscopy and Imaging Center (UMIC), which is supported by NWO grants 40-00506-98-9021 and 175-010-2009-023.