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

// Zhaohui Zhong 1, 2, * , Huiying Gu 2, * , Jirun Peng 3, 4 , Wenzheng Wang 1 , Brian H. Johnstone 5, 6 , Keith L. March 5, 6, 7, 8 , Martin R. Farlow 2 , Yansheng Du 2, 9 1 Department of General Surgery, Peking University People’s Hospital, Beijing 100044, PR China 2 Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, USA 3 Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, PR China 4 Ninth Clinical Medical College of Peking University, Beijing 100038, PR China 5 Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA 6 Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA 7 Krannert Institute of Cardiology, Indianapolis, IN 46202, USA 8 VA Center for Regenerative Medicine, Indina University School of Medicine, Indianapolis, IN 46202, USA 9 School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA * These authors have contributed equally to this work Correspondence to: Yansheng Du, e-mail: ydu@iupui.edu Jirun Peng, e-mail: pengjr@medmail.com.cn Keywords: ASC-CM, GDNF, VEGF, angiogenesis, hepatocellular carcinoma Received: October 08, 2015     Accepted: April 16, 2016     Published: May 6, 2016 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.