title: Mesenchymal stem cells do not exert direct beneficial effects on CNS remyelination in the absence of the peripheral immune system.
abstract: Remyelination is the natural repair mechanism in demyelinating disorders such as multiple sclerosis (MS) and it was proposed that it might protect from axonal loss. For unknown reasons, remyelination is often incomplete or fails in MS lesions and therapeutic treatments to enhance remyelination are not available. Recently, the transplantation of exogenous mesenchymal stem cells (MSC) has emerged as a promising tool to enhance repair processes. This included the animal model experimental autoimmune encephalomyelitis (EAE), a commonly used model for the autoimmune mechanisms of MS. However, in EAE it is not clear if the beneficial effect of MSC derives from a direct influence on brain resident cells or if this is an indirect phenomenon via modulation of the peripheral immune system. The aim of this study was to determine potential regenerative functions of MSC in the toxic cuprizone model of demyelination that allows studying direct effects on de- and remyelination without the influence of the peripheral immune system. MSC from three different species (human, murine, canine) were transplanted either intraventricularly into the cerebrospinal fluid or directly into the lesion of the corpus callosum at two time points: at the onset of oligodendrocyte progenitor cell (OPC) proliferation or the peak of OPC proliferation during cuprizone induced demyelination. Our results show that MSC did not exert any regenerative effects after cuprizone induced demyelination and oligodendrocyte loss. During remyelination, MSC did not influence the dynamics of OPC proliferation and myelin formation. In conclusion, MSC did not exert direct regenerative functions in a mouse model where peripheral immune cells and especially T lymphocytes do not play a role. We thus suggest that the peripheral immune system is required for MSC to exert their effects and this is independent from a direct influence of the central nervous system.
authors.affiliation: Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Germany; Center for Systems Neuroscience, Hannover, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Salinas Tejedor
authors.affiliation: Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Germany.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Berner
authors.affiliation: Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Jacobsen
authors.affiliation: Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Germany; Center for Systems Neuroscience, Hannover, Germany.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Gudi
authors.affiliation: Center for Systems Neuroscience, Hannover, Germany; Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Jungwirth
authors.affiliation: Center for Systems Neuroscience, Hannover, Germany; Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Hansmann
authors.affiliation: Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gingele
authors.affiliation: Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Germany.
authors.forename: Chittappen K
authors.initials: CK
authors.lastname: Prajeeth
authors.affiliation: Center for Systems Neuroscience, Hannover, Germany; Department of Pathology, University of Veterinary Medicine Hannover, Hannover, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Baumgärtner
authors.affiliation: Department of Orthopaedic Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hoffmann
authors.affiliation: Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Skripuletz
authors.affiliation: Clinical Neuroimmunology and Neurochemistry, Department of Neurology, Hannover Medical School, Germany; Center for Systems Neuroscience, Hannover, Germany. Electronic address: stangel.martin@MH-Hannover.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Stangel
mesh_terms: D000818:Animals; D003337:Corpus Callosum / Q000473:pathology / Q000503:physiopathology*; D003471:Cuprizone; D004285:Dogs; D006801:Humans; D007107:Immune System / Q000503:physiopathology*; D007276:Injections, Intraventricular; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000502:physiology; D009103:Multiple Sclerosis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D009186:Myelin Sheath / Q000473:pathology / Q000502:physiology*; D009836:Oligodendroglia / Q000502:physiology
chemical_list: D003471:Cuprizone
keywords: Corpus callosum; Cuprizone; Intraventricular; MS; MSC