Journal Article

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

Yang, Xue-wen, Sun, Li-hua, Zhu, Yan-meng, Jiao, Lei, Yu, Qi, Li, Xin, Shao, Ying-chun, Xuan, Li-na, Tan, Zhong-yue, Zhang, Ming-yu, Pan, Zhen-wei, Li, Hao-dong, Zhang, Yi-yuan, Gong, Man-yu, Zhang, Xiao-fang, Yang, Bao-feng, Li, Qing-qi, Li, Meng-meng, Liu, Yun-qi, Liu, Dong-hua, Zhang, Ying, Zhang, Yuan-yuan, Wang, Yan-ying, Li, Zhange, Zhang, Yong

2023

Overview

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.

• Publisher: Springer Nature Singapore,Nature Publishing Group
• Subject: Animals / Biomedical and Life Sciences / Biomedicine / Biopsy / Bone Morphogenetic Proteins - metabolism / Chemokine CXCL12 - drug effects / Chemokine CXCL12 - metabolism / Diabetes / Diabetes mellitus / Diabetes Mellitus, Experimental - complications / Diabetes Mellitus, Experimental - drug therapy / Diabetes Mellitus, Experimental - metabolism / Diabetes Mellitus, Type 2 - drug therapy / Diabetes Mellitus, Type 2 - metabolism / Endothelial Progenitor Cells - metabolism / Endothelial Progenitor Cells - pathology / Genetic engineering / Growth differentiation factor 11 / Growth Differentiation Factors - metabolism / Growth Differentiation Factors - therapeutic use / Homing behavior / Humans / Hypoxia-Inducible Factor 1, alpha Subunit - drug effects / Hypoxia-Inducible Factor 1, alpha Subunit - metabolism / Immunology / Internal Medicine / Medical Microbiology / Mice / Molecular modelling / Neovascularization, Physiologic / Pharmacology/Toxicology / Progenitor cells / Recombinant Proteins - metabolism / Recombinant Proteins - therapeutic use / Regeneration / siRNA / Skin / Topical application / Vaccine / Vascular endothelial growth factor / Vascular Endothelial Growth Factor A - drug effects / Vascular Endothelial Growth Factor A - metabolism / Vascularization / Wound healing / Wound Healing - drug effects