School of Biomedical Engineering (Suzhou), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu, China.
Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, Jiangsu, China.
Metabolism. 2023 Mar;140:155398. doi: 10.1016/j.metabol.2023.155398. Epub 2023 Jan 7.
Cell therapy with mesenchymal stem cells (MSCs) and biomaterials holds great potential for the treatment of diabetic ulceration; however, the underlying mechanism as well as its compatibility with the first-line anti-diabetic drug, metformin (MTF), has not been well elucidated.
MSCs derived from the umbilical cord were labeled with fluorescent proteins, followed by transplantation in a fibrin scaffold (MSCs/FG) onto the STZ-induced diabetic wound in a C57BL6/J mouse model. MTF was administered by oral gavage at a dose of 250 mg/kg/day. The wound healing rate, epithelization, angiogenesis, and underlying mechanism were evaluated in MSCs/FG- and MTF-treated diabetic wounds. Moreover, the dose-dependent effects of MTF and involvement of the Akt/mTOR pathway were analyzed in keratinocyte and fibroblast cultures.
MSCs/FG significantly promoted angiogenesis in diabetic wound healing without signs of differentiation or integration. The recruitment of fibroblasts and keratinocytes by MSCs/FG promotes migration and vascular endothelial growth factor (VEGF) expression in an Akt/mTOR-dependent manner. MTF, which is generally considered a mTOR inhibitor, displayed dose-dependent effects on MSC-unregulated Akt/mTOR and VEGF expression. Oral administration of MTF at an anti-diabetic dosage synergistically acted with MSCs/FG to promote Akt/mTOR activation, VEGF expression, and subsequent angiogenesis in diabetic wounds; however, it reduced the survival of MSCs.
Our study identifies that MTF coordinates with mesenchymal cells to promote Akt/mTOR activation and VEGF-mediated angiogenesis during diabetic wound healing. These findings offer new insights into MSCs engraftment in FG scaffolds for diabetic wound healing and provide support for the promotion of MSCs therapy in patients prescribed with MTF.
间充质干细胞（MSCs）与生物材料的细胞疗法在治疗糖尿病溃疡方面具有巨大潜力；然而，其潜在机制以及与一线抗糖尿病药物二甲双胍（MTF）的兼容性尚未得到充分阐明。
从脐带中分离出的间充质干细胞（MSCs）被荧光蛋白标记，然后移植到 STZ 诱导的糖尿病小鼠模型的纤维蛋白支架（MSCs/FG）上。MTF 通过口服灌胃给药，剂量为 250mg/kg/天。在 MSCs/FG 和 MTF 处理的糖尿病伤口中评估了伤口愈合率、上皮化、血管生成和潜在机制。此外，还分析了 MTF 的剂量依赖性作用以及 Akt/mTOR 通路的参与在角质形成细胞和成纤维细胞培养物中的作用。
MSCs/FG 显著促进了糖尿病伤口愈合中的血管生成，而没有分化或整合的迹象。MSCs/FG 募集的成纤维细胞和角质形成细胞通过 Akt/mTOR 依赖性方式促进迁移和血管内皮生长因子（VEGF）表达。通常被认为是 mTOR 抑制剂的 MTF 对 MSC 调节的 Akt/mTOR 和 VEGF 表达表现出剂量依赖性作用。口服给予 MTF 的抗糖尿病剂量与 MSCs/FG 协同作用，促进 Akt/mTOR 激活、VEGF 表达和糖尿病伤口中的血管生成；然而，它降低了 MSCs 的存活率。
我们的研究表明，MTF 与间充质细胞协调作用，在糖尿病伤口愈合过程中促进 Akt/mTOR 激活和 VEGF 介导的血管生成。这些发现为 FG 支架中 MSCs 移植治疗糖尿病伤口提供了新的见解，并为促进 MTF 治疗患者的 MSCs 治疗提供了支持。
