Inhibition of phosphodiesterase-4 promotes oligodendrocyte precursor cell differentiation and enhances CNS remyelination

Authors

  • Yasir A. Syed,

    1. Wellcome Trust and MRC Cambridge Stem Cell Institute, and Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, West Forvie Building, Forvie Site, Robinson Way, Cambridge, UK
    2. Department of Neurosurgery, Medical University Vienna, Vienna, Austria
    3. Max-Planck Institute for Experimental Medicine, Department of Neurogenetics, Goettingen, Germany
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    • These authors contributed equally to this work.
  • Alexandra Baer,

    1. Department of Neurosurgery, Medical University Vienna, Vienna, Austria
    2. Department of Pediatrics, Medical University Vienna, Vienna, Austria
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    • These authors contributed equally to this work.
  • Matthias P. Hofer,

    1. Wellcome Trust and MRC Cambridge Stem Cell Institute, and Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, West Forvie Building, Forvie Site, Robinson Way, Cambridge, UK
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  • Ginez A. González,

    1. Wellcome Trust and MRC Cambridge Stem Cell Institute, and Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, West Forvie Building, Forvie Site, Robinson Way, Cambridge, UK
    2. Wellcome Trust and MRC Cambridge Stem Cell Institute, and Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, UK
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  • Jon Rundle,

    1. Wellcome Trust and MRC Cambridge Stem Cell Institute, and Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, West Forvie Building, Forvie Site, Robinson Way, Cambridge, UK
    2. Wellcome Trust and MRC Cambridge Stem Cell Institute, and Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, UK
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  • Szymon Myrta,

    1. Wellcome Trust and MRC Cambridge Stem Cell Institute, and Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, West Forvie Building, Forvie Site, Robinson Way, Cambridge, UK
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  • Jeffrey K. Huang,

    1. Wellcome Trust and MRC Cambridge Stem Cell Institute, and Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, UK
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  • Chao Zhao,

    1. Wellcome Trust and MRC Cambridge Stem Cell Institute, and Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, UK
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  • Moritz J. Rossner,

    1. Max-Planck-Institute for Experimental Medicine, Research Group ‘Gene Expression and Signalling’, Department of Neurogenetics, Göttingen, Germany
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  • Matthew W. B. Trotter,

    1. Wellcome Trust and MRC Cambridge Stem Cell Institute, and Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, West Forvie Building, Forvie Site, Robinson Way, Cambridge, UK
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  • Gert Lubec,

    1. Department of Pediatrics, Medical University Vienna, Vienna, Austria
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  • Robin J. M. Franklin,

    Corresponding author
    1. Wellcome Trust and MRC Cambridge Stem Cell Institute, and Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, UK
    • Corresponding author: Tel: +44 1223 747476; Fax: +44 1223 763350;

      E-mail: mrk25@cam.ac.uk

      Corresponding author: Tel: +44 1223 337642; Fax: +44 1223 337610;

      E-mail: rjf1000@cam.ac.uk

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  • Mark R. Kotter

    Corresponding author
    1. Wellcome Trust and MRC Cambridge Stem Cell Institute, and Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, West Forvie Building, Forvie Site, Robinson Way, Cambridge, UK
    2. Department of Neurosurgery, Medical University Vienna, Vienna, Austria
    3. Max-Planck Institute for Experimental Medicine, Department of Neurogenetics, Goettingen, Germany
    • Corresponding author: Tel: +44 1223 747476; Fax: +44 1223 763350;

      E-mail: mrk25@cam.ac.uk

      Corresponding author: Tel: +44 1223 337642; Fax: +44 1223 337610;

      E-mail: rjf1000@cam.ac.uk

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Abstract

The increasing effectiveness of new disease-modifying drugs that suppress disease activity in multiple sclerosis has opened up opportunities for regenerative medicines that enhance remyelination and potentially slow disease progression. Although several new targets for therapeutic enhancement of remyelination have emerged, few lend themselves readily to conventional drug development. Here, we used transcription profiling to identify mitogen-activated protein kinase (Mapk) signalling as an important regulator involved in the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes. We show in tissue culture that activation of Mapk signalling by elevation of intracellular levels of cyclic adenosine monophosphate (cAMP) using administration of either dibutyryl-cAMP or inhibitors of the cAMP-hydrolysing enzyme phosphodiesterase-4 (Pde4) enhances OPC differentiation. Finally, we demonstrate that systemic delivery of a Pde4 inhibitor leads to enhanced differentiation of OPCs within focal areas of toxin-induced demyelination and a consequent acceleration of remyelination. These data reveal a novel approach to therapeutic enhancement of remyelination amenable to pharmacological intervention and hence with significant potential for translation.

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