Peroxisome proliferator-activated receptor γ ligands regulate neural stem cell proliferation and differentiation in vitro and in vivo

Authors

  • Jose A. Morales-Garcia,

    1. Instituto de Investigaciones Biomédicas, CSIC-UAM, Arturo Duperier 4, 28029-Madrid, Spain
    2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Spain
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  • Rosario Luna-Medina,

    1. Instituto de Investigaciones Biomédicas, CSIC-UAM, Arturo Duperier 4, 28029-Madrid, Spain
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  • Clara Alfaro-Cervello,

    1. Unidad Mixta Centro de Investigación Príncipe Felipe - Universidad de Valencia, Spain
    2. Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense de Madrid, 28040-Madrid, Spain
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  • Marta Cortes-Canteli,

    1. Instituto de Investigaciones Biomédicas, CSIC-UAM, Arturo Duperier 4, 28029-Madrid, Spain
    Current affiliation:
    1. Department of Neurobiology and Genetics, The Rockefeller University, New York, NY
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  • Angel Santos,

    1. Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense de Madrid, 28040-Madrid, Spain
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  • Jose M. Garcia-Verdugo,

    1. Unidad Mixta Centro de Investigación Príncipe Felipe - Universidad de Valencia, Spain
    2. Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense de Madrid, 28040-Madrid, Spain
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  • Ana Perez-Castillo

    Corresponding author
    1. Instituto de Investigaciones Biomédicas, CSIC-UAM, Arturo Duperier 4, 28029-Madrid, Spain
    2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) Spain
    • Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid. Arturo Duperier, 4. 28029-Madrid, Spain
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Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) belongs to a family of ligand-activated nuclear receptors and its ligands are known to control many physiological and pathological situations. Its role in the central nervous system has been under intense analysis during the last years. Here we show a novel function for PPARγ in controlling stem cell expansion in the adult mammalian brain. Adult rats treated with pioglitazone, a specific ligand of PPARγ, had elevated numbers of proliferating progenitor cells in the subventricular zone and the rostral migratory stream. Electron microscopy analysis also showed important changes in the subventricular zone ultrastructure of pioglitazone-treated animals including an increased number of migratory cell chains. These results were further confirmed in vitro. Neurosphere assays revealed significant increases in the number of neurosphere forming cells from pioglitazone- and rosiglitazone (two specific ligands of PPARγ receptor)-treated cultures that exhibited enhanced capacity for cell migration and differentiation. The effects of pioglitazone were blocked by the PPARγ receptor antagonists GW9662 and T0070907, suggesting that its effects are mediated by a mechanism dependent on PPARγ activation. These results indicate for the first time that activation of PPARγ receptor directly regulates proliferation, differentiation, and migration of neural stem cells in vivo. © 2010 Wiley-Liss, Inc.

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