Autocrine VEGF drives neural stem cell proximity to the adult hippocampus vascular niche

Abstract

The vasculature is a key component of adult brain neural stem cell (NSC) niches. In the adult mammalian hippocampus, NSCs reside in close contact with a dense capillary network. How this niche is maintained is unclear. We recently found that adult hippocampal NSCs express VEGF, a soluble factor with chemoattractive properties for vascular endothelia. Here, we show that global and NSC-specific VEGF loss led to dissociation of NSCs and their intermediate progenitor daughter cells from local vasculature. Surprisingly, though, we found no changes in local vascular density. Instead, we found that NSC-derived VEGF supports maintenance of gene expression programs in NSCs and their progeny related to cell migration and adhesion. In vitro assays revealed that blockade of VEGF receptor 2 impaired NSC motility and adhesion. Our findings suggest that NSCs maintain their own proximity to vasculature via self-stimulated VEGF signaling that supports their motility towards and/or adhesion to local blood vessels.

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“…The NSC secretome promotes the regeneration of nervous tissue, particularly SC: improving the survival of recipient nerve cells, neuroplasticity and neuroimmune modulation ( Dause et al, 2022 ). The autocrine mechanism consists of synthesising cytokines, growth factors and extracellular matrix molecules by stem cells for their self-maintenance, cell migration and adhesion ( Dause et al, 2024 ). Autocrine regulation is ensured by activation of the expression of sonic hedgehog (SHH), platelet derived growth factor (PDGF), chondroitin sulfate proteoglycans (CSPGs), apolipoprotein E (ApoE) and pituitary adenylate cyclase-activating peptide (PACAP), vascular endothelial growth factor (VEGF), insulin-like growth factor 2 (IGF2), milk fat globule-EGF 8 (MFGE8), Wingless and Int-1 (WNT), glycosylated cystatin C (CCg) and stem cell-derived neural stem/progenitor cell supporting factor (SDNSF).…”

“…Autocrine regulation is ensured by activation of the expression of sonic hedgehog (SHH), platelet derived growth factor (PDGF), chondroitin sulfate proteoglycans (CSPGs), apolipoprotein E (ApoE) and pituitary adenylate cyclase-activating peptide (PACAP), vascular endothelial growth factor (VEGF), insulin-like growth factor 2 (IGF2), milk fat globule-EGF 8 (MFGE8), Wingless and Int-1 (WNT), glycosylated cystatin C (CCg) and stem cell-derived neural stem/progenitor cell supporting factor (SDNSF). Also, NSCs secrete aggrecans, neurocans, and phosphocans, which increase the survival of NSCs in the recipient’s tissue ( Gong et al, 2020 ; Dause et al, 2022 ; 2024 ). Moreover, through a paracrine mechanism, NSCs can regulate the microenvironment under pathological conditions ( Wang et al, 2019 ; Zhang et al, 2020 ; Pajer et al, 2021 ); due to the paracrine mechanism, NSCs can perform intercellular responses.…”