title: M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination.
abstract: The lack of therapies for progressive multiple sclerosis highlights the need to understand the regenerative process of remyelination that can follow CNS demyelination. This involves an innate immune response consisting of microglia and macrophages, which can be polarized to distinct functional phenotypes: pro-inflammatory (M1) and anti-inflammatory or immunoregulatory (M2). We found that a switch from an M1- to an M2-dominant response occurred in microglia and peripherally derived macrophages as remyelination started. Oligodendrocyte differentiation was enhanced in vitro with M2 cell conditioned media and impaired in vivo following intra-lesional M2 cell depletion. M2 cell densities were increased in lesions of aged mice in which remyelination was enhanced by parabiotic coupling to a younger mouse and in multiple sclerosis lesions that normally show remyelination. Blocking M2 cell-derived activin-A inhibited oligodendrocyte differentiation during remyelination in cerebellar slice cultures. Thus, our results indicate that M2 cell polarization is essential for efficient remyelination and identify activin-A as a therapeutic target for CNS regeneration.
authors.affiliation: MRC Centre for Regenerative Medicine/MS Society Centre for Translational Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Veronique E
authors.initials: VE
authors.lastname: Miron
authors.affiliation: MRC Centre for Regenerative Medicine/MS Society Centre for Translational Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Amanda
authors.initials: A
authors.lastname: Boyd
authors.affiliation: Wellcome Trust and MRC Cambridge Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Jing-Wei
authors.initials: JW
authors.lastname: Zhao
authors.affiliation: MRC Centre for Regenerative Medicine/MS Society Centre for Translational Research, University of Edinburgh, Edinburgh, UK.|Wellcome Trust and MRC Cambridge Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Tracy J
authors.initials: TJ
authors.lastname: Yuen
authors.affiliation: Wellcome Trust and MRC Cambridge Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Julia M
authors.initials: JM
authors.lastname: Ruckh
authors.affiliation: Howard Hughes Medical Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Harvard Stem Cell Institute & Joslin Diabetes Center, Cambridge, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Shadrach
authors.affiliation: Wellcome Trust and MRC Cambridge Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: van Wijngaarden
authors.affiliation: Howard Hughes Medical Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Harvard Stem Cell Institute & Joslin Diabetes Center, Cambridge, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
authors.affiliation: MRC Centre for Regenerative Medicine/MS Society Centre for Translational Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Williams
authors.affiliation: Wellcome Trust and MRC Cambridge Stem Cell Institute and Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Robin J M
authors.initials: RJM
authors.lastname: Franklin
authors.affiliation: MRC Centre for Regenerative Medicine/MS Society Centre for Translational Research, University of Edinburgh, Edinburgh, UK.
authors.forename: Charles
authors.initials: C
authors.lastname: Ffrench-Constant
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000831:Animals, Newborn; D019256:Cadmium Chloride / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects / Q000473:pathology*; D004002:Clodronic Acid / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003711:Demyelinating Diseases / Q000473:pathology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000502:physiology*; D008875:Middle Aged; D009185:Myelin Proteins / Q000378:metabolism; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000187:drug effects / Q000502:physiology*
chemical_list: D017077:Culture Media, Conditioned; D009185:Myelin Proteins; D004002:Clodronic Acid; D019256:Cadmium Chloride