Reversible neural stem cell niche dysfunction in a model of multiple sclerosis
Article first published online: 9 MAR 2011
Copyright © 2011 American Neurological Association
Annals of Neurology
Volume 69, Issue 5, pages 878–891, May 2011
How to Cite
Rasmussen, S., Imitola, J., Ayuso-Sacido, A., Wang, Y., Starossom, S. C., Kivisäkk, P., Zhu, B., Meyer, M., Bronson, R. T., Garcia-Verdugo, J. M. and Khoury, S. J. (2011), Reversible neural stem cell niche dysfunction in a model of multiple sclerosis. Ann Neurol., 69: 878–891. doi: 10.1002/ana.22299
- Issue published online: 22 APR 2011
- Article first published online: 9 MAR 2011
- Accepted manuscript online: 28 OCT 2010 07:32AM EST
- Manuscript Accepted: 11 OCT 2010
- Manuscript Revised: 4 OCT 2010
- Manuscript Received: 22 APR 2010
- National Institutes of Health. Grant Numbers: AI46374, AI043496
- National Multiple Sclerosis Society. Grant Number: RG 3945
- a Fidelity Foundation grant
- National Multiple Sclerosis Society. Grant Number: PP1239
- a faculty PhD scholarship from the University of Southern Denmark
- a grant from Hørslev Fonden, Denmark
- a grant from Red Terapia Regenerativa, Spain
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.
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.
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.
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