title: Drug-based modulation of endogenous stem cells promotes functional remyelination in vivo.
abstract: Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes. These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention. To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells. Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro. Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro. Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients.
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Fadi J
authors.initials: FJ
authors.lastname: Najm
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Mayur
authors.initials: M
authors.lastname: Madhavan
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Zaremba
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Shick
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Robert T
authors.initials: RT
authors.lastname: Karl
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Factor
authors.affiliation: 1] Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA [2] Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA [3] Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Tyler E
authors.initials: TE
authors.lastname: Miller
authors.affiliation: Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Zachary S
authors.initials: ZS
authors.lastname: Nevin
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kantor
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Alex
authors.initials: A
authors.lastname: Sargent
authors.affiliation: PerkinElmer, 940 Winter Street, Waltham, Massachusetts 02451, USA.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Quick
authors.affiliation: Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Schlatzer
authors.affiliation: Drug Discovery Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45237, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Tang
authors.affiliation: Drug Discovery Center, University of Cincinnati College of Medicine, Cincinnati, Ohio 45237, USA.
authors.forename: Ruben
authors.initials: R
authors.lastname: Papoian
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Brimacombe
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Shen
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Boxer
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA.
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Avenue, Chicago, Illinois 60611, USA.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Robinson
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Avenue, Chicago, Illinois 60611, USA.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Podojil
authors.affiliation: Department of Microbiology-Immunology and Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Avenue, Chicago, Illinois 60611, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Miller
authors.affiliation: 1] Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA [2] Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Tesar
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002990:Clobetasol / Q000494:pharmacology*; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005260:Female; D005855:Germ Layers / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008244:Lysophosphatidylcholines; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008825:Miconazole / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D009186:Myelin Sheath / Q000187:drug effects* / Q000378:metabolism*; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects; D046509:Tissue Culture Techniques
chemical_list: D008244:Lysophosphatidylcholines; D011965:Receptors, Glucocorticoid; D008825:Miconazole; D002990:Clobetasol; D020928:Mitogen-Activated Protein Kinases