Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice
Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice
复制标题
DOI：
10.1172/jci36858
复制
发表时间：
2010-12-01
影响因子：
15.9
通讯作者：
Chen, Alex F.
中科院分区：
文献类型：
--
作者：
Marrotte, Eric J.;Chen, Dan-Dan;Chen, Alex F.
由于伤口愈合受损而导致的截肢是糖尿病的严重并发症。血管生成不足导致糖尿病患者伤口愈合不良。内皮祖细胞（EPCs）通常增强血管生成和伤口修复，但在糖尿病患者中功能受损。在这里，我们报告，锰超氧化物歧化酶（MnSOD）在EPCs的表达减少有助于受损的2型糖尿病小鼠模型的伤口愈合。在2型糖尿病（db/db）小鼠中检测到循环EPCs的频率降低，并且当分离时，这些细胞表现出MnSOD的表达和活性降低。与正常对照组相比，糖尿病小鼠的伤口愈合和血管生成明显延迟。对于细胞治疗，局部移植内皮祖细胞到切除伤口的糖尿病小鼠表明，糖尿病内皮祖细胞是不如正常内皮祖细胞在加速伤口愈合的有效性。MnSOD基因治疗后移植的糖尿病EPCs恢复其介导血管生成和伤口修复的能力。相反，siRNA介导的正常EPCs中MnSOD的敲低降低了它们在糖尿病伤口愈合试验中的活性。增加移植糖尿病EPCs的数量也提高了伤口闭合率。我们的研究结果表明，在2型糖尿病小鼠模型中，使用离体MnSOD基因转移后的糖尿病EPCs进行细胞治疗可加速其愈合伤口的能力。
Amputation as a result of impaired wound healing is a serious complication of diabetes. Inadequate angiogenesis contributes to poor wound healing in diabetic patients. Endothelial progenitor cells (EPCs) normally augment angiogenesis and wound repair but are functionally impaired in diabetics. Here we report that decreased expression of manganese superoxide dismutase (MnSOD) in EPCs contributes to impaired would healing in a mouse model of type 2 diabetes. A decreased frequency of circulating EPCs was detected in type 2 diabetic (db/db) mice, and when isolated, these cells exhibited decreased expression and activity of MnSOD. Wound healing and angiogenesis were markedly delayed in diabetic mice compared with normal controls. For cell therapy, topical transplantation of EPCs onto excisional wounds in diabetic mice demonstrated that diabetic EPCs were less effective than normal EPCs at accelerating wound closure. Transplantation of diabetic EPCs after MnSOD gene therapy restored their ability to mediate angiogenesis and wound repair. Conversely, siRNA-mediated knockdown of MnSOD in normal EPCs reduced their activity in diabetic wound healing assays. Increasing the number of transplanted diabetic EPCs also improved the rate of wound closure. Our findings demonstrate that cell therapy using diabetic EPCs after ex vivo MnSOD gene transfer accelerates their ability to heal wounds in a mouse model of type 2 diabetes.