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

EMBO Molecular Medicine

Jose R. Pineda²  Mathieu Daynac²  Alexandra Chicheportiche²  Arantxa Cebrian-Silla³  Karine Sii Felice²  Jose Manuel Garcia-Verdugo³  François D. Boussin¹ 

[1] E-mail address: 关键词: aging;    endothelial cells;    irradiation;    neural stem cells;    TGF‐beta;   

DOI  :  10.1002/emmm.201202197

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
Copyright © 2013 EMBO Molecular Medicine

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.