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

Area of Science:

• Neuroscience
• Stem Cell Biology
• Molecular Signaling

Background:

• Adult neural stem cells (NSCs) in the dentate gyrus (DG) are crucial for hippocampal function.
• Vascular endothelial growth factor (VEGF) is implicated in NSC maintenance, but its signaling mechanism remains unclear.
• Conflicting studies exist regarding VEGF's role and signaling in adult NSCs.

Purpose of the Study:

• To elucidate the precise mechanism of VEGF signaling in adult DG NSCs.
• To determine if VEGF acts intracrine (intracellular) or paracrine (extracellular) in these cells.
• To resolve discrepancies in previous research on VEGF and adult neurogenesis.

Main Methods:

• Utilized cell culture assays with adult DG NSCs.
• Investigated intracellular and extracellular VEGF signaling pathways.
• Employed sheddase inhibitors to restore extracellular VEGF signaling.
• Analyzed NSC-VEGF loss in cultured cells and intact mice.

Main Results:

• Identified an intracrine VEGF-VEGFR2 signaling pathway within adult DG NSCs.
• Demonstrated that intracellular VEGF, but not extracellular VEGF, stimulates signaling cascades.
• Found that sheddase-mediated cleavage of VEGFR2 prevents extracellular VEGF signaling.
• Observed that NSC-VEGF loss leads to NSC exhaustion, impaired migration, and reduced vascular proximity.

Conclusions:

• Adult DG NSCs exclusively utilize an intracrine VEGF signaling mechanism.
• This intracellular pathway is critical for preventing NSC exhaustion and maintaining vascular association.
• The cellular source and localization of VEGF dictate its functional impact on DG NSCs.