GDF11 promotes wound healing in diabetic mice via stimulating HIF-1ɑ-VEGF/SDF-1ɑ-mediated endothelial progenitor cell mobilization and neovascularization

Ying Zhang1, Yi-yuan Zhang1, Zhen-wei Pan1, Qing-qi Li1, Li-hua Sun1, Xin Li2, Man-yu Gong1, Xue-wen Yang1, Yan-ying Wang1, Hao-dong Li1, Li-na Xuan1, Ying-chun Shao1, Meng-meng Li1, Ming-yu Zhang1, Qi Yu1, Zhange Li1, Xiao-fang Zhang1, Dong-hua Liu1, Yan-meng Zhu1, Zhong-yue Tan1, Yuan-yuan Zhang1, Yun-qi Liu1, Yong Zhang1, Lei Jiao1, Bao-feng Yang1,3
1 Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin 150081, China
2 Department of Cardiovascular Sciences, School of Engineering, University of Leicester, Leicester, UK
3 Department of Pharmacology and Therapeutics, Melbourne School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia
Correspondence to: Lei Jiao:, Bao-feng Yang:,
DOI: 10.1038/s41401-022-01013-2
Received: 14 June 2022
Accepted: 12 October 2022
Advance online: 8 November 2022


Non-healing diabetic wounds (DW) are a serious clinical problem that remained poorly understood. We recently found that topical application of growth differentiation factor 11 (GDF11) accelerated skin wound healing in both Type 1 DM (T1DM) and genetically engineered Type 2 diabetic db/db (T2DM) mice. In the present study, we elucidated the cellular and molecular mechanisms underlying the action of GDF11 on healing of small skin wound. Single round-shape full-thickness wound of 5-mm diameter with muscle and bone exposed was made on mouse dorsum using a sterile punch biopsy 7 days following the onset of DM. Recombinant human GDF11 (rGDF11, 50 ng/mL, 10 μL) was topically applied onto the wound area twice a day until epidermal closure (maximum 14 days). Digital images of wound were obtained once a day from D0 to D14 post-wounding. We showed that topical application of GDF11 accelerated the healing of full-thickness skin wounds in both type 1 and type 2 diabetic mice, even after GDF8 (a muscle growth factor) had been silenced. At the cellular level, GDF11 significantly facilitated neovascularization to enhance regeneration of skin tissues by stimulating mobilization, migration and homing of endothelial progenitor cells (EPCs) to the wounded area. At the molecular level, GDF11 greatly increased HIF-1ɑ expression to enhance the activities of VEGF and SDF-1ɑ, thereby neovascularization. We found that endogenous GDF11 level was robustly decreased in skin tissue of diabetic wounds. The specific antibody against GDF11 or silence of GDF11 by siRNA in healthy mice mimicked the non-healing property of diabetic wound. Thus, we demonstrate that GDF11 promotes diabetic wound healing via stimulating endothelial progenitor cells mobilization and neovascularization mediated by HIF-1ɑ-VEGF/SDF-1ɑ pathway. Our results support the potential of GDF11 as a therapeutic agent for non-healing DW.
Keywords: diabetic wound; GDF11; endothelial progenitor cell; neovascularization; HIF-1ɑ; VEGF/SDF-1α

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