Intracrine VEGF Signaling Is Required for Adult Hippocampal Neural Stem Cell Maintenance and Vascular Proximity

Adult neural stem cells (NSCs) in the mammalian dentate gyrus (DG) of the hippocampus rely on multiple signals for their preservation throughout the lifespan. While several studies have suggested that vascular endothelial growth factor (VEGF), in particular VEGF synthesized by NSCs themselves, is critical for NSC maintenance and adult neurogenesis, conflicting studies have left it uncertain how VEGF signals to NSCs. Here, we identified a VEGF-VEGFR2 intracrine signaling mechanism within adult DG NSCs that prevents NSC exhaustion and supports their proximity to local blood vessels. Using cell culture assays, we show that while intracellular VEGF stimulated receptor signaling cascades, extracellular VEGF did not. We found that this primary reliance on intracellular VEGF receptor signaling was most likely due to sheddase-mediated cleavage of extracellular VEGFR2 ligand binding domains, as phospho-signaling in response to extracellular VEGF could be restored using sheddase inhibitors. Using cultured adult DG NSCs and intact mice, we further show that NSC-VEGF loss caused cell-autonomous exhaustion of adult DG NSCs, along with impaired migration in cultured NSCs and reduced proximity of NSCs to local blood vessels in mouse DG. Our findings support an exclusively intracellular mechanism for VEGF signaling in adult DG NSCs, thereby providing resolution to previously conflicting studies and suggesting that cellular source can dictate the functional impact of soluble ligands in DG NSCs.