Endothelial NT-3 Delivered by Vasculature and CSF Promotes Quiescence of Subependymal Neural Stem Cells through Nitric Oxide Induction

• Published in: Neuron (Cambridge, Mass.) Mass.), 2014-08, Vol.83 (3), p.572-585
• Main Authors: Delgado, Ana C., Ferrón, Sacri R., Vicente, Diana, Porlan, Eva, Perez-Villalba, Ana, Trujillo, Carmen M., D′Ocón, Pilar, Fariñas, Isabel
• Format: Article
• Language: English
• Subjects: Animals; Antigens; Behavior; Cell Differentiation - physiology; Cell Proliferation - physiology; Cell Survival - physiology; Cells, Cultured; Deoxyribonucleic acid; DNA; Endothelial Cells - metabolism; Kinases; Mice; Neural Stem Cells - cytology; Neurons - cytology; Neurotrophin 3 - metabolism; Nitric Oxide - cerebrospinal fluid; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Rodents
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2014.06.015

Interactions of adult neural stem cells (NSCs) with supportive vasculature appear critical for their maintenance and function, although the molecular details are still under investigation. Neurotrophin (NT)-3 belongs to the NT family of trophic factors, best known for their effects in promoting neuronal survival. Here we show that NT-3 produced and secreted by endothelial cells of brain and choroid plexus capillaries is required for the quiescence and long-term maintenance of NSCs in the mouse subependymal niche. Uptake of NT-3 from irrigating vasculature and cerebrospinal fluid (CSF) induces the rapid phosphorylation of endothelial nitric oxide (NO) synthase present in the NSCs, leading to the production of NO, which subsequently acts as a cytostatic factor. Our results identify a novel interaction between stem cells and vasculature/CSF compartments that is mediated by an unprecedented role of a neurotrophin and indicate that stem cells can regulate their own quiescence in response to endothelium-secreted molecules. •NT-3 produced by endothelia reduces proliferation of activated NSCs•NT-3 from vasculature and CSF is required for the long-term maintenance of NSCs•NT-3 induces the production of NO by endothelial nitric oxide synthase in NSCs•The pathway identifies a requirement for NSCs to proliferate in perivascular/periventricular niches Adult neural stem cells reside and proliferate in perivascular/periventricular niches. Delgado et al. show that the cells can regulate their own quiescence and maintenance through nitric oxide generation but this requires exposure to endothelium-derived neurotrophin-3 present in vasculature and cerebrospinal fluid.