1Department of Surgery, Vascular Medicine Institute, McGowan Institute of Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
J Clin Invest. 2010 Dec;120(12):4207-19. doi: 10.1172/JCI36858. Epub 2010 Nov 8.
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.
由于伤口愈合受损而导致的截肢是糖尿病的一种严重并发症。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) 通常可增强血管生成和伤口修复，但在糖尿病患者中其功能受损。在这里，我们报告 EPCs 中锰超氧化物歧化酶 (MnSOD) 的表达减少导致 2 型糖尿病小鼠模型中的伤口愈合受损。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，将 EPC 局部移植到糖尿病小鼠的切除伤口上表明，与正常 EPC 相比，糖尿病 EPC 在加速伤口闭合方面的效果较差。MnSOD 基因治疗后的糖尿病 EPC 移植恢复了它们介导血管生成和伤口修复的能力。相反，在糖尿病伤口愈合测定中，用 siRNA 介导的 MnSOD 敲低降低了正常 EPC 的活性。增加移植的糖尿病 EPC 的数量也提高了伤口闭合的速度。我们的研究结果表明，使用糖尿病 EPC 进行体外 MnSOD 基因转移后的细胞治疗可加速其在 2 型糖尿病小鼠模型中愈合伤口的能力。
