Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice.
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.
1Department of Surgery, Vascular Medicine Institute, McGowan Institute of Regenerative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Eric J
EJ
Marrotte
Dan-Dan
DD
Chen
Jeffrey S
JS
Hakim
Alex F
AF
Chen
D000818:Animals; D048909:Diabetes Complications / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology* / Q000637:transplantation; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000201:enzymology; D013482:Superoxide Dismutase / Q000235:genetics*; D014945:Wound Healing / Q000235:genetics* / Q000502:physiology*
D013482:Superoxide Dismutase