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

Ann Neurol. 2011 May;69(5):878-91. doi: 10.1002/ana.22299. Epub 2011 Mar 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Bromodeoxyuridine / metabolism
  • Cell Count / methods
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Encephalomyelitis, Autoimmune, Experimental / chemically induced
  • Encephalomyelitis, Autoimmune, Experimental / drug therapy
  • Encephalomyelitis, Autoimmune, Experimental / pathology*
  • Encephalomyelitis, Autoimmune, Experimental / physiopathology
  • Mice
  • Microglia / drug effects
  • Microglia / pathology
  • Microglia / ultrastructure
  • Microscopy, Electron, Transmission
  • Minocycline / pharmacology
  • Multiple Sclerosis
  • Myelin Proteolipid Protein / adverse effects
  • Neural Stem Cells / drug effects
  • Neural Stem Cells / physiology*
  • Neural Stem Cells / ultrastructure
  • Oligodendroglia / drug effects
  • Oligodendroglia / physiology
  • Peptide Fragments / adverse effects
  • Secondary Prevention
  • Stem Cell Niche / drug effects
  • Stem Cell Niche / pathology*
  • Time Factors


  • Anti-Bacterial Agents
  • Myelin Proteolipid Protein
  • Peptide Fragments
  • myelin proteolipid protein (139-151)
  • Minocycline
  • Bromodeoxyuridine