Jiake Mo,1,2,* Jiaqi Zhang,1,2,* Xubiao Meng,3 Fang Wang,1,2 Weian Tang,1,2 Ying Liu,1,2 Lanfang Fu,3 Fang Liang,4 Zhaohui Mo1,2 

1Department of Endocrinology, Third Xiangya Hospital of Central South University, Changsha, Hunan Province, People’s Republic of China; 2Diabetic Foot Research Center of Central South University, Changsha, Hunan Province, People’s Republic of China; 3Department of Endocrinology, Haikou People’s Hospital & Haikou Affiliated Hospital of Central South University Xiangya School of Medicine, Haikou, Hainan Province, People’s Republic of China; 4Department of Endocrinology, Xingtai People’s Hospital, Xingtai, Hebei Province, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Zhaohui Mo; Fang Liang, Email easd04mzh@126.com; liangfang1024@163.com

Introductions: Diabetic foot ulcers (DFU) are notoriously difficult to heal, however, its underlying molecular mechanisms are unknown. MicroRNA-139-5p participates in various biological processes, including cancer and vascular endothelial injury, while its role in diabetic wound healing has not been reported.
Methods: Sprague-Dawley (SD) rats were intraperitoneally injected with streptozotocin and a 1.0 cm full-layer dorsal skin wound was made to establish a diabetic wound model. On days 1, 4, 7, and 10 after the wound was made, a solution containing microRNA-139-5p antagomir or control was injected along the dorsal edge of the wound. Wound healing was analyzed using Image J, histological analysis and molecular analysis. Skin tissues from 4 diabetic and 4 matched non-diabetic ulcer patients were obtained to detect microRNA-139-5p expression. In vitro, human skin fibroblasts were transfected with microRNA-139-5p inhibitors/mimics, the function of the fibroblasts was evaluated by CCK-8 assay and scratch assay, and AP-1 (c-Fos/c-Jun) was detected.
Results: Obviously elevated microRNA-139-5p expression was detected in the wound tissue of the rats with diabetes and patients with DFUs, and the microRNA-139-5p antagonist-treated diabetic wounds had faster healing rates. The pace of diabetic wound re-epithelialization and angiogenesis was accelerated, and the expression of AP-1 family members (c-Fos/c-Jun), and VEGF, PDGF was upregulated in the wound tissue of diabetic rats treated with topical microRNA-139-5p antagomir. In vitro, the expression of microRNA-139-5p was up-regulated in human skin fibroblasts induced by high glucose treatment, while the function of the cell proliferation and migration was promoted and the level of AP-1 (c-Fos/c-Jun) was increased after transfected with the microRNA-139-5p inhibitor, and vice versa. Our study further verified that microRNA-139-5p regulated the migration of human skin fibroblasts by modulating c-Fos.
Conclusion: Inhibiting microRNA-139-5p improves fibroblasts viability and promotes diabetic wound healing, suggesting that this may be a therapeutic strategy for diabetic foot ulcer.

Keywords: miR-139-5p, diabetes, wound healing, AP-1, fibroblasts