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
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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