Vascular-derived TGF-β increases in the stem cell niche and perturbs neurogenesis during aging and following irradiation in the adult mouse brain

Authors

  • Jose R. Pineda,

    1. CEA DSV iRCM SCSR, Laboratoire de Radiopathologie, Fontenay-aux-Roses, France
    2. INSERM, U967, Fontenay-aux-Roses, France
    3. Université Paris Diderot, Sorbonne Paris Cité, UMR 967, Fontenay-aux-Roses, France
    4. Université Paris Sud, UMR 967, Fontenay-aux-Roses, France
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  • Mathieu Daynac,

    1. CEA DSV iRCM SCSR, Laboratoire de Radiopathologie, Fontenay-aux-Roses, France
    2. INSERM, U967, Fontenay-aux-Roses, France
    3. Université Paris Diderot, Sorbonne Paris Cité, UMR 967, Fontenay-aux-Roses, France
    4. Université Paris Sud, UMR 967, Fontenay-aux-Roses, France
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  • Alexandra Chicheportiche,

    1. CEA DSV iRCM SCSR, Laboratoire de Radiopathologie, Fontenay-aux-Roses, France
    2. INSERM, U967, Fontenay-aux-Roses, France
    3. Université Paris Diderot, Sorbonne Paris Cité, UMR 967, Fontenay-aux-Roses, France
    4. Université Paris Sud, UMR 967, Fontenay-aux-Roses, France
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  • Arantxa Cebrian-Silla,

    1. Laboratorio de Neurobiología Comparada, Instituto Cavanilles, Universidad de Valencia, Valencia, CIBERNED, Spain
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  • Karine Sii Felice,

    1. CEA DSV iRCM SCSR, Laboratoire de Radiopathologie, Fontenay-aux-Roses, France
    2. INSERM, U967, Fontenay-aux-Roses, France
    3. Université Paris Diderot, Sorbonne Paris Cité, UMR 967, Fontenay-aux-Roses, France
    4. Université Paris Sud, UMR 967, Fontenay-aux-Roses, France
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  • Jose Manuel Garcia-Verdugo,

    1. Laboratorio de Neurobiología Comparada, Instituto Cavanilles, Universidad de Valencia, Valencia, CIBERNED, Spain
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  • François D. Boussin,

    Corresponding author
    1. CEA DSV iRCM SCSR, Laboratoire de Radiopathologie, Fontenay-aux-Roses, France
    2. INSERM, U967, Fontenay-aux-Roses, France
    3. Université Paris Diderot, Sorbonne Paris Cité, UMR 967, Fontenay-aux-Roses, France
    4. Université Paris Sud, UMR 967, Fontenay-aux-Roses, France
    • Tel: +33 1 46 54 94 61; Fax: +33 1 46 54 91 80

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    • These authors contributed equally to this work.

  • Marc-André Mouthon

    Corresponding author
    1. CEA DSV iRCM SCSR, Laboratoire de Radiopathologie, Fontenay-aux-Roses, France
    2. INSERM, U967, Fontenay-aux-Roses, France
    3. Université Paris Diderot, Sorbonne Paris Cité, UMR 967, Fontenay-aux-Roses, France
    4. Université Paris Sud, UMR 967, Fontenay-aux-Roses, France
    • Tel: +33 1 46 54 94 61; Fax: +33 1 46 54 91 80

    Search for more papers by this author
    • These authors contributed equally to this work.


Abstract

Neurogenesis decreases during aging and following cranial radiotherapy, causing a progressive cognitive decline that is currently untreatable. However, functional neural stem cells remained present in the subventricular zone of high dose-irradiated and aged mouse brains. We therefore investigated whether alterations in the neurogenic niches are perhaps responsible for the neurogenesis decline. This hypothesis was supported by the absence of proliferation of neural stem cells that were engrafted into the vascular niches of irradiated host brains. Moreover, we observed a marked increase in TGF-β1 production by endothelial cells in the stem cell niche in both middle-aged and irradiated mice. In co-cultures, irradiated brain endothelial cells induced the apoptosis of neural stem/progenitor cells via TGF-β/Smad3 signalling. Strikingly, the blockade of TGF-β signalling in vivo using a neutralizing antibody or the selective inhibitor SB-505124 significantly improved neurogenesis in aged and irradiated mice, prevented apoptosis and increased the proliferation of neural stem/progenitor cells. These findings suggest that anti-TGF-β-based therapy may be used for future interventions to prevent neurogenic collapse following radiotherapy or during aging.

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