Zhu Ying-Jie, Chen Hu-Lin, Huang Jing-Kai, Cai Xin-Jie, Zhan Bang-le
Department of Dermatology, Southern University of Science and Technology Hospital, Shenzhen, Guangdong, China.
Department of Dermatology, Guangdong Women and Children Hospital, Guangzhou, Guangdong, China.
J Cosmet Dermatol. 2024 Dec;23(12):4230-4238. doi: 10.1111/jocd.16486. Epub 2024 Aug 21.
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK), a member of tumor necrosis factor superfamily, can bind to fibroblast growth factor-inducible 14 (Fn14) receptor and stimulate angiogenesis. The interaction between epidermal growth factor receptor (EGFR) and endothelial growth factor (EGF) leads to EGFR signal transduction and promotes angiogenesis. The objective of this study was to explore whether TWEAK participated in the diabetic skin wound healing by regulating Fn14/EGFR signaling.
Human umbilical vein endothelial cells (HUVECs) were treated with 35 mmol/L d-glucose and classified into the Control Group, High Glucose (HG) Group and HG + TWEAK Group. Then, the TWEAK expression and the proliferation, migration and tubule formation of HUVECs were detected, respectively. In vivo experiment, the diabetic model was established by injecting streptozotocin (STZ, 50 mg/kg) into male BALB/c mice. On the back of successfully modeled diabetic mice, a full-thickness skin wound of 6 mm diameter was formed. Then, the mice were randomly assigned into three groups: Blank Group, Phosphate Buffer Saline (PBS) Group, and TWEAK Group. Subsequently, expression levels of TWEAK, Fn14, EGFR and vascular endothelial growth factor (VEGF)-A were measured, and the CD31 expression in the wounded skin tissue of mice was checked by immunohistochemistry staining.
The expression level of TWEAK in HUVECs of HG Group decreased significantly, as well as the viability, migration, and tubule formation of cells. After over-expression of TWEAK, the cell viability, migration, and tubule formation abilities of HUVECs recovered remarkably. In vivo, the wound healing rate of diabetic mice was raised, the neovascularization was increased, and the CD31 expression in the wounded tissue was obviously upregulated after injection with recombinant TWEAK antibody.
TWEAK stimulates angiogenesis and accelerates the wound healing of diabetic skin by regulating Fn14/EGFR signaling.
肿瘤坏死因子样凋亡微弱诱导剂（TWEAK）是肿瘤坏死因子超家族成员，可与成纤维细胞生长因子诱导14（Fn14）受体结合并刺激血管生成。表皮生长因子受体（EGFR）与内皮生长因子（EGF）之间的相互作用导致EGFR信号转导并促进血管生成。本研究的目的是探讨TWEAK是否通过调节Fn14/EGFR信号通路参与糖尿病皮肤伤口愈合。
将人脐静脉内皮细胞（HUVECs）用35 mmol/L D-葡萄糖处理，并分为对照组、高糖（HG）组和HG+TWEAK组。然后，分别检测HUVECs中TWEAK的表达以及细胞的增殖、迁移和小管形成情况。在体内实验中，通过向雄性BALB/c小鼠注射链脲佐菌素（STZ，50 mg/kg）建立糖尿病模型。在成功建模的糖尿病小鼠背部形成直径为6 mm的全层皮肤伤口。然后，将小鼠随机分为三组：空白组、磷酸盐缓冲盐水（PBS）组和TWEAK组。随后，检测TWEAK、Fn14、EGFR和血管内皮生长因子（VEGF）-A的表达水平，并通过免疫组织化学染色检查小鼠伤口皮肤组织中的CD31表达。
HG组HUVECs中TWEAK的表达水平显著降低，细胞的活力、迁移和小管形成能力也降低。TWEAK过表达后，HUVECs的细胞活力、迁移和小管形成能力明显恢复。在体内，注射重组TWEAK抗体后，糖尿病小鼠的伤口愈合率提高，新生血管形成增加，伤口组织中的CD31表达明显上调。
TWEAK通过调节Fn14/EGFR信号通路刺激血管生成并加速糖尿病皮肤伤口愈合。
