title: Transcript profiling of different types of multiple sclerosis lesions yields FGF1 as a promoter of remyelination.
abstract: Chronic demyelination is a pathological hallmark of multiple sclerosis (MS). Only a minority of MS lesions remyelinates completely. Enhancing remyelination is, therefore, a major aim of future MS therapies. Here we took a novel approach to identify factors that may inhibit or support endogenous remyelination in MS. We dissected remyelinated, demyelinated active, and demyelinated inactive white matter MS lesions, and compared transcript levels of myelination and inflammation-related genes using quantitative PCR on customized TaqMan Low Density Arrays. In remyelinated lesions, fibroblast growth factor (FGF) 1 was the most abundant of all analyzed myelination-regulating factors, showed a trend towards higher expression as compared to demyelinated lesions and was significantly higher than in control white matter. Two MS tissue blocks comprised lesions with adjacent de- and remyelinated areas and FGF1 expression was higher in the remyelinated rim compared to the demyelinated lesion core. In functional experiments, FGF1 accelerated developmental myelination in dissociated mixed cultures and promoted remyelination in slice cultures, whereas it decelerated differentiation of purified primary oligodendrocytes, suggesting that promotion of remyelination by FGF1 is based on an indirect mechanism. The analysis of human astrocyte responses to FGF1 by genome wide expression profiling showed that FGF1 induced the expression of the chemokine CXCL8 and leukemia inhibitory factor, two factors implicated in recruitment of oligodendrocytes and promotion of remyelination. Together, this study presents a transcript profiling of remyelinated MS lesions and identified FGF1 as a promoter of remyelination. Modulation of FGF family members might improve myelin repair in MS.
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich, Marchioninistraße 15, D-81377, Munich, Germany. hema.mohan@ukmuenster.de.|Present address: Department of Neurology, University of Münster, Münster, Germany. hema.mohan@ukmuenster.de.
authors.forename: Hema
authors.initials: H
authors.lastname: Mohan
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich, Marchioninistraße 15, D-81377, Munich, Germany. anita.friese@web.de.
authors.forename: Anita
authors.initials: A
authors.lastname: Friese
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany. stefanie.albrecht@ukmuenster.de.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Albrecht
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich, Marchioninistraße 15, D-81377, Munich, Germany. markus.krumbholz@med.uni-muenchen.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Krumbholz
authors.affiliation: Division of Clinical Neurosciences, University of Glasgow, Glasgow, UK. Christina.Elliott@glasgow.ac.uk.
authors.forename: Christina L
authors.initials: CL
authors.lastname: Elliott
authors.affiliation: Division of Clinical Neurosciences, University of Glasgow, Glasgow, UK. ariel.arthur@gmail.com.
authors.forename: Ariel
authors.initials: A
authors.lastname: Arthur
authors.affiliation: Division of Neuroscience, Institute of Experimental Neurology (INSpe), San Raffaele Scientific Institute, Milan, Italy. menon.ramesh@hsr.it.
authors.forename: Ramesh
authors.initials: R
authors.lastname: Menon
authors.affiliation: Division of Neuroscience, Institute of Experimental Neurology (INSpe), San Raffaele Scientific Institute, Milan, Italy. farina.cinthia@hsr.it.
authors.forename: Cinthia
authors.initials: C
authors.lastname: Farina
authors.affiliation: Institute for Neuropathology, Göttingen, Germany. andreas.junker@med.uni-goettingen.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Junker
authors.affiliation: Institute for Neuropathology, Göttingen, Germany. cstadelmann@med.uni-goettingen.de.
authors.forename: Christine
authors.initials: C
authors.lastname: Stadelmann
authors.affiliation: Division of Clinical Neurosciences, University of Glasgow, Glasgow, UK. Susan.Barnett@glasgow.ac.uk.
authors.forename: Susan C
authors.initials: SC
authors.lastname: Barnett
authors.affiliation: The Netherlands Brain Bank, Netherlands Institute for Neuroscience, Amsterdam, Netherlands. i.huitinga@nin.knaw.nl.
authors.forename: Inge
authors.initials: I
authors.lastname: Huitinga
authors.affiliation: Max Planck Institute of Neurobiology, Hertie Senior Professorship, Martinsried, Germany. Hartmut.Wekerle@med.uni-muenchen.de.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Wekerle
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich, Marchioninistraße 15, D-81377, Munich, Germany. Reinhard.Hohlfeld@med.uni-muenchen.de.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany. Reinhard.Hohlfeld@med.uni-muenchen.de.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Hohlfeld
authors.affiliation: Center for Brain Research, Medical University of Vienna, Vienna, Austria. hans.lassmann@meduniwien.ac.at.
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany. Tanja.Kuhlmann@ukmuenster.de.
authors.forename: Tanja
authors.initials: T
authors.lastname: Kuhlmann
authors.affiliation: Division of Clinical Neurosciences, University of Glasgow, Glasgow, UK. Christopher.Linington@glasgow.ac.uk.
authors.forename: Chris
authors.initials: C
authors.lastname: Linington
authors.affiliation: Institute of Clinical Neuroimmunology, Ludwig Maximilian University Munich, Marchioninistraße 15, D-81377, Munich, Germany. edgar.meinl@med.uni-muenchen.de.
authors.forename: Edgar
authors.initials: E
authors.lastname: Meinl
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000502:physiology; D001921:Brain / Q000503:physiopathology*; D002478:Cells, Cultured; D016220:Fibroblast Growth Factor 1 / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000503:physiopathology*; D009186:Myelin Sheath / Q000502:physiology*; D009836:Oligodendroglia / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013116:Spinal Cord / Q000503:physiopathology*; D046509:Tissue Culture Techniques; D066127:White Matter / Q000503:physiopathology
chemical_list: C508606:CXCL8 protein, human; D016209:Interleukin-8; D053605:Leukemia Inhibitory Factor; D012333:RNA, Messenger; D016220:Fibroblast Growth Factor 1