GDNF secreted from adipose-derived stem cells stimulates VEGF-independent angiogenesis

Abstract

Adipose tissue stroma contains a population of mesenchymal stem cells (MSC) promote new blood vessel formation and stabilization. These adipose-derived stem cells (ASC) promote de novo formation of vascular structures in vitro. We investigated the angiogenic factors secreted by ASC and discovered that glial-derived neurotrophic factor (GDNF) is a key mediator for endothelial cell network formation. It was found that both GDNF alone or present in ASC-conditioned medium (ASC-CM) stimulated capillary network formation by using human umbilical vein endothelial cells (HUVECs) and such an effect was totally independent of vascular endothelial growth factor (VEGF) activity. Additionally, we showed stimulation of capillary network formation by GDNF, but not VEGF, could be blocked by the Ret (rearranged during transfection) receptor antagonist RPI-1, a GDNF signaling inhibitor. Furthermore, GDNF were found to be overexpressed in cancer cells that were resistant to the anti-angiogenic treatment using the VEGF antibody. Cancer cells in the liver hepatocellular carcinoma (HCC), a non-nervous related cancer, highly overexpressed GDNF as compared to normal liver cells. Our data strongly suggest that, in addition to VEGF, GDNF secreted by ASC and HCC cells, may be another important factor promoting pathological neovascularization. Thus, GDNF may be a potential therapeutic target for HCC and obesity treatments.

Neurotrophic factor and Trk signaling mechanisms underlying the promotion of motor recovery after acute spinal cord injury in rats

“…NFs are important for spinal cord recovery, neuronal survival and regeneration, synaptic regeneration, and limb motor function after SCI (5–8). However, the effect of NFs after SCI has not been well defined.…”

Isolation of endothelial progenitor cells from human adipose tissue

“…Several recent studies have indicated that adipose-derived regenerative cells (ADRCs) can differentiate into pericytes in vitro and in vivo (Amos et al, 2008;Traktuev et al, 2008;Zannettino et al, 2008). However, transplantation of ADSCs, as well as SVFs, have demonstrated neoangiogenesis and vasculogenesis in vivo (Guo et al, 2016;Zhong et al, 2016). Based on these reports, we hypothesized that ADSCs do not differentiate into EPCs, but that SVFs may contain an EPC population.…”

Role of the Renal Microcirculation in Progression of Chronic Kidney Injury in Obesity

“…Alternatively, it is possible that based on their different biochemical profile, adipose tissues outside the kidney and fat infiltration into the renal parenchyma represent competing forces. Adipose tissue may not only serve as source of numerous cytokines, but can also modulate their effects on mobilization and actions of renal resident mesenchymal cells towards physiological cell turnover[60, 61], pathological angiogenesis[62], reparative angiogenesis[63], or vascular rarefaction and tissue damage[64]. …”

“…For example, a novel factor that may serve as a powerful instigator of aberrant angiogenesis is glial-derived neurotrophic factor (GDNF). A recent study shows that GDNF promotes pathological neovascularization by stimulating endothelial cell network formation in a VEGF-independent fashion, implying GDNF may be a target for obesity-induced organ damage[62]. …”