Abstract：
Impaired wound healing in diabetes results from a complex interplay of factors that disrupt epithelialization and wound closure. MG53, a tripartite motif (TRIM) family protein, plays a key role in repairing cell membrane damage and facilitating tissue regeneration. In this study, bone marrow-derived mesenchymal stem cells (BMSCs) were transduced with lentiviral vectors overexpressing MG53 to investigate their efficacy in diabetic wound healing. Using a db/db mouse wound model, we observed that BMSCs-MG53 significantly enhanced diabetic wound healing. This improvement was associated with marked increase in re-epithelialization and vascularization. BMSCs-MG53 promoted recruitment and survival of BMSCs, as evidenced by an increase in MG53/Ki67-positive BMSCs and their improved response to scratch wounding. The combination therapy also promoted angiogenesis in diabetic wound tissues by upregulating the expression of angiogenic growth factors. MG53 overexpression accelerated the differentiation of BMSCs into endothelial cells, manifested as the formation of mature vascular network structure and a remarkable increase in DiI-Ac-LDL uptake. Our mechanistic investigation revealed that MG53 binds to caveolin-3 (CAV3) and subsequently increases phosphorylation of eNOS, thereby activating eNOS/NO signaling. Notably, CAV3 knockdown reversed the promoting effects of MG53 on BMSCs endothelial differentiation. Overall, our findings support the notion that MG53 binds to CAV3, activates eNOS/NO signaling pathway, and accelerates the therapeutic effect of BMSCs in the context of diabetic wound healing. These insights hold promise for the development of innovative strategies for treating diabetic-related impairments in wound healing.
摘要：
糖尿病中受损的伤口愈合是由破坏上皮形成和伤口闭合的因素的复杂相互作用引起的。MG53，一个三方基序（TRIM）家族蛋白，在修复细胞膜损伤和促进组织再生中起关键作用。在这项研究中,用过表达MG53的慢病毒载体转导骨髓间充质干细胞（BMSCs），以研究其在糖尿病伤口愈合中的功效。使用db/db鼠标伤口模型，我们观察到BMSCs-MG53能显著促进糖尿病创面愈合。这种改善与上皮再形成和血管形成的显着增加有关。BMSCs-MG53促进BMSCs募集和存活,MG53/Ki67阳性BMSCs的增加及其对抓伤的改善反应证明了这一点。联合疗法还通过上调血管生成生长因子的表达来促进糖尿病伤口组织中的血管生成。MG53过表达加速了BMSCs向内皮细胞的分化,表现为成熟的血管网络结构的形成和DiI-Ac-LDL摄取的显着增加。我们的机制研究表明，MG53与caveolin-3（CAV3）结合，随后增加eNOS的磷酸化，从而激活eNOS/NO信号。值得注意的是,CAV3敲低可逆转MG53对BMSCs内皮分化的促进作用。总的来说,我们的发现支持MG53与CAV3结合，激活eNOS/NO信号通路，并加速BMSCs在糖尿病伤口愈合的背景下的治疗效果。这些见解为开发用于治疗伤口愈合中的糖尿病相关损伤的创新策略提供了希望。
