title: Vascular-derived TGF-β increases in the stem cell niche and perturbs neurogenesis during aging and following irradiation in the adult mouse brain.
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.
authors.affiliation: CEA DSV iRCM SCSR, Laboratoire de Radiopathologie, Fontenay-aux-Roses, France.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Pineda
authors.forename: Mathieu
authors.initials: M
authors.lastname: Daynac
authors.forename: Alexandra
authors.initials: A
authors.lastname: Chicheportiche
authors.forename: Arantxa
authors.initials: A
authors.lastname: Cebrian-Silla
authors.forename: Karine
authors.initials: K
authors.lastname: Sii Felice
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Garcia-Verdugo
authors.forename: François D
authors.initials: FD
authors.lastname: Boussin
authors.forename: Marc-André
authors.initials: MA
authors.lastname: Mouthon
mesh_terms: D000375:Aging / Q000378:metabolism* / Q000528:radiation effects; D000818:Animals; D001921:Brain / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism / Q000528:radiation effects*; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects; D055495:Neurogenesis / Q000528:radiation effects*; D015398:Signal Transduction / Q000528:radiation effects; D055153:Stem Cell Niche; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016212:Transforming Growth Factor beta