Vascular‐derived TGF‐β increases in the stem cell niche and perturbs neurogenesis during aging and following irradiation in the adult mouse brain
Male
0301 basic medicine
Medicine (General)
Aging
Neurogenesis
QH426-470
Mice
03 medical and health sciences
R5-920
Neural Stem Cells
Transforming Growth Factor beta
TGF‐beta
Genetics
Animals
Humans
Stem Cell Niche
Research Articles
neural stem cells
Cell Proliferation
0303 health sciences
irradiation
aging
Brain
Endothelial Cells
endothelial cells
Mice, Inbred C57BL
Signal Transduction
DOI:
10.1002/emmm.201202197
Publication Date:
2013-03-25T06:56:55Z
AUTHORS (8)
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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