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

• Published in: EMBO molecular medicine Vol. 5; no. 4; pp. 548 - 562
• Main Authors: Pineda, Jose R., Daynac, Mathieu, Chicheportiche, Alexandra, Cebrian‐Silla, Arantxa, Sii Felice, Karine, Garcia‐Verdugo, Jose Manuel, Boussin, François D., Mouthon, Marc‐André
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2013; WILEY‐VCH Verlag; EMBO Press; WILEY-VCH Verlag; Springer Nature
• Subjects: Aging; Aging - metabolism; Aging - radiation effects; Alzheimer's disease; Animals; Apoptosis; Brain - cytology; Brain - growth & development; Brain - metabolism; Brain - radiation effects; Brain cancer; Cell Proliferation; Cognitive ability; Endothelial cells; Endothelial Cells - metabolism; Experiments; Humans; irradiation; Male; Mice; Mice, Inbred C57BL; Neural stem cells; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neural Stem Cells - radiation effects; Neurogenesis; Neurogenesis - radiation effects; Progenitor cells; Radiation therapy; Research Article; Signal Transduction - radiation effects; Smad3 protein; Stem Cell Niche; Stem cell transplantation; Stem cells; Subventricular zone; TGF‐beta; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Transforming growth factor-b1; France; endothelial cells; aging; neural stem cells; TGF‐beta; irradiation
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.1002/emmm.201202197

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. Graphical Abstract In aged or irradiated mice, the neural stem cell vascular niche expresses increased levels of TGFbeta1, which induces apoptosis of neural stem cells via Smad3. Treatment with TGFbeta signaling blockers restores neurogenesis in these mice.