Reversible neural stem cell niche dysfunction in a model of multiple sclerosis

Authors

  • Stine Rasmussen PhD,

    1. Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    2. Department of Anatomy and Neurobiology, University of Southern Denmark, Odense, Denmark
    Search for more papers by this author
  • Jaime Imitola MD,

    1. Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    Search for more papers by this author
  • Angel Ayuso-Sacido PhD,

    1. Department of Comparative Neurobiology, Cavanilles Institute, University of Valencia, Valencia, Spain
    2. Department of Cellular Therapy, Prince Felipe Center of Investigation, Valencia, Spain
    Search for more papers by this author
  • Yue Wang MD, PhD,

    1. Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    Search for more papers by this author
  • Sarah C. Starossom,

    1. Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    Search for more papers by this author
  • Pia Kivisäkk MD,

    1. Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    Search for more papers by this author
  • Bing Zhu PhD,

    1. Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    Search for more papers by this author
  • Morten Meyer PhD,

    1. Department of Anatomy and Neurobiology, University of Southern Denmark, Odense, Denmark
    Search for more papers by this author
  • Roderick T. Bronson DVM,

    1. Department of Pathology, Harvard Medical School, Boston, MA
    Search for more papers by this author
  • Jose Manuel Garcia-Verdugo PhD,

    1. Department of Comparative Neurobiology, Cavanilles Institute, University of Valencia, Valencia, Spain
    2. Department of Cellular Therapy, Prince Felipe Center of Investigation, Valencia, Spain
    Search for more papers by this author
  • Samia J. Khoury MD

    Corresponding author
    1. Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
    • 77 Avenue Louis Pasteur, Room 712, Harvard Institutes of Medicine, Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA 02115
    Search for more papers by this author

Abstract

Objective

The subventricular zone (SVZ) of the brain constitutes a niche for neural stem and progenitor cells that can initiate repair after central nervous system (CNS) injury. In a relapsing-remitting model of experimental autoimmune encephalomyelitis (EAE), the neural stem cells (NSCs) become activated and initiate regeneration during acute disease, but lose this ability during the chronic phases of disease. We hypothesized that chronic microglia activation contributes to the failure of the NSC repair potential in the SVZ.

Methods

Using bromodeoxyuridine injections at different time points during EAE, we quantified the number of proliferating and differentiating progenitors, and evaluated the structure of the SVZ by electron microscopy. In vivo minocycline treatment during EAE was used to address the effect of microglia inactivation on SVZ dysfunction.

Results

In vivo treatment with minocycline, an inhibitor of microglia activation, increases stem cell proliferation in both naive and EAE animals. Minocycline treatment decreases cortical and periventricular pathology in the chronic phase of EAE, improving the proliferation of Sox2 stem cells and NG2 oligodendrocyte precursors cells originating in the SVZ and their differentiation into mature oligodendrocytes.

Interpretation

These data suggest that failure of repair observed during chronic EAE correlates with microglia activation and that treatments targeting chronic microglial activation have the potential for enhancing repair in the CNS. ANN NEUROL 2011

Ancillary