Cell Rep. 2015 Feb 17. pii: S2211-1247(15)00074-1. doi: 10.1016/j.celrep.2015.01.049. [Epub ahead of print]

Vascular Endothelial Growth Factor Receptor 3 Controls Neural Stem Cell Activation in Mice and Humans.

Han J¹, Calvo CF², Kang TH³, Baker KL¹, Park JH³, Parras C², Levittas M², Birba U², Pibouin-Fragner L¹, Fragner P¹, Bilguvar K⁴, Duman RS⁵, Nurmi H⁶,Alitalo K⁶, Eichmann AC⁷, Thomas JL⁸.

Abstract

Neural stem cells (NSCs) continuously produce new neurons within the adult mammalian hippocampus. NSCs are typically quiescent but activated to self-renew or differentiate into neural progenitor cells. The molecular mechanisms of NSC activation remain poorly understood. Here, we show that adult hippocampal NSCs express vascular endothelial growth factor receptor (VEGFR) 3 and its ligand VEGF-C, which activates quiescent NSCs to enter the cell cycle and generate progenitor cells. Hippocampal NSC activation and neurogenesis are impaired by conditional deletion of Vegfr3 in NSCs. Functionally, this is associated with compromised NSC activation in response to VEGF-C and physical activity. In NSCs derived from humanembryonic stem cells (hESCs), VEGF-C/VEGFR3 mediates intracellular activation of AKT and ERK pathways that control cell fate and proliferation. These findings identify VEGF-C/VEGFR3 signaling as a specific regulator of NSC activation and neurogenesis in mammals.