title: Antibody-mediated neutralization of myelin-associated EphrinB3 accelerates CNS remyelination.
abstract: Remyelination in multiple sclerosis (MS) lesions often remains incomplete despite the presence of oligodendrocyte progenitor cells (OPCs). Amongst other factors, successful remyelination depends on the phagocytic clearance of myelin debris. However, the proteins in myelin debris that act as potent and selective inhibitors on OPC differentiation and inhibit CNS remyelination remain unknown. Here, we identify the transmembrane signalling protein EphrinB3 as important mediator of this inhibition, using a protein analytical approach in combination with a primary rodent OPC assay. In the presence of EphrinB3, OPCs fail to differentiate. In a rat model of remyelination, infusion of EphrinB3 inhibits remyelination. In contrast, masking EphrinB3 epitopes using antibodies promotes remyelination. Finally, we identify EphrinB3 in MS lesions and demonstrate that MS lesion extracts inhibit OPC differentiation while antibody-mediated masking of EphrinB3 epitopes promotes it. Our findings suggest that EphrinB3 could be a target for therapies aiming at promoting remyelination in demyelinating disease.
authors.affiliation: Wellcome Trust and MRC Cambridge Stem Cell Institute, Department of Clinical Neurosciences, Anne McLaren Laboratory, University of Cambridge, Cambridge, CB2 0SZ, UK.|Department of Neurogenetics, Max Planck Institute for Experimental Medicine, 37075, Goettingen, Germany.
authors.forename: Yasir A
authors.initials: YA
authors.lastname: Syed
authors.affiliation: Wellcome Trust and MRC Cambridge Stem Cell Institute, Department of Clinical Neurosciences, Anne McLaren Laboratory, University of Cambridge, Cambridge, CB2 0SZ, UK.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Centre for Neuroregeneration, Chancellor's Building, 49 Little France Crescent, Edinburgh, EH16 4SB, UK.
authors.forename: Don
authors.initials: D
authors.lastname: Mahad
authors.affiliation: Department of Neurogenetics, Max Planck Institute for Experimental Medicine, 37075, Goettingen, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Möbius
authors.affiliation: Department of Chemistry, University of Natural Resource and Life Sciences, Muthgasse 18, 1190, Vienna, Austria.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Altmann
authors.affiliation: Frankfurt Institute for Molecular Life Sciences and Institute of Cell Biology and Neuroscience, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438, Frankfurt am Main, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Foss
authors.forename: G A
authors.initials: GA
authors.lastname: González
authors.affiliation: Frankfurt Institute for Molecular Life Sciences and Institute of Cell Biology and Neuroscience, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438, Frankfurt am Main, Germany.
authors.forename: Aycan
authors.initials: A
authors.lastname: Sentürk
authors.affiliation: Frankfurt Institute for Molecular Life Sciences and Institute of Cell Biology and Neuroscience, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438, Frankfurt am Main, Germany.
authors.forename: Amparo
authors.initials: A
authors.lastname: Acker-Palmer
authors.affiliation: Department of Pediatrics, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.|Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 4, 1090, Vienna, Austria.
authors.forename: Gert
authors.initials: G
authors.lastname: Lubec
authors.affiliation: Cambridge Centre for Proteomics, Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Lilley
authors.affiliation: Wellcome Trust and MRC Cambridge Stem Cell Institute, Department of Clinical Neurosciences, Anne McLaren Laboratory, University of Cambridge, Cambridge, CB2 0SZ, UK.
authors.forename: Robin J M
authors.initials: RJM
authors.lastname: Franklin
authors.affiliation: Department of Neurogenetics, Max Planck Institute for Experimental Medicine, 37075, Goettingen, Germany.
authors.forename: Klaus-A
authors.initials: KA
authors.lastname: Nave
authors.affiliation: Wellcome Trust and MRC Cambridge Stem Cell Institute, Department of Clinical Neurosciences, Anne McLaren Laboratory, University of Cambridge, Cambridge, CB2 0SZ, UK. mrk25@cam.ac.uk.|Department of Neurogenetics, Max Planck Institute for Experimental Medicine, 37075, Goettingen, Germany. mrk25@cam.ac.uk.|Universitätsmedizin Göttingen, Universitätsklinik für Neurochirurgie, Robert-Koch-Straße 40, 37075, Göttingen, Germany. mrk25@cam.ac.uk.
authors.forename: Mark R N
authors.initials: MRN
authors.lastname: Kotter
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D036389:Ephrin-B3 / Q000235:genetics / Q000378:metabolism*; D000939:Epitopes / Q000378:metabolism; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000378:metabolism* / Q000473:pathology; D009186:Myelin Sheath / Q000378:metabolism* / Q000473:pathology; D009416:Nerve Regeneration / Q000502:physiology; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D055495:Neurogenesis / Q000502:physiology; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D036122:Receptor, EphA4 / Q000378:metabolism
chemical_list: D036389:Ephrin-B3; D000939:Epitopes; D036122:Receptor, EphA4
keywords: EphrinB3; Multiple sclerosis; Oligodendrocytes; Remyelination