Research Papers:

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

Zhaohui Zhong _, Huiying Gu, Jirun Peng, Wenzheng Wang, Brian H. Johnstone, Keith L. March, Martin R. Farlow and Yansheng Du

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Oncotarget. 2016; 7:36829-36841. https://doi.org/10.18632/oncotarget.9208

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Zhaohui Zhong1,2,*, Huiying Gu2,*, Jirun Peng3,4, Wenzheng Wang1, Brian H. Johnstone5,6, Keith L. March5,6,7,8, Martin R. Farlow2, Yansheng Du2,9

1Department of General Surgery, Peking University People’s Hospital, Beijing 100044, PR China

2Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, USA

3Department of Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, PR China

4Ninth Clinical Medical College of Peking University, Beijing 100038, PR China

5Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA

6Indiana Center for Vascular Biology and Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA

7Krannert Institute of Cardiology, Indianapolis, IN 46202, USA

8VA Center for Regenerative Medicine, Indina University School of Medicine, Indianapolis, IN 46202, USA

9School of Health Sciences, Purdue University, West Lafayette, IN 47907, USA

*These authors have contributed equally to this work

Correspondence to:

Yansheng Du, e-mail: [email protected]

Jirun Peng, e-mail: [email protected]

Keywords: ASC-CM, GDNF, VEGF, angiogenesis, hepatocellular carcinoma

Received: October 08, 2015    Accepted: April 16, 2016    Published: May 6, 2016


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.

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