Editors' ChoiceDiabetes

MnSOD, Angiogenesis, and Wounds: Let the Healing Begin!

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Science Translational Medicine  24 Nov 2010:
Vol. 2, Issue 59, pp. 59ec181
DOI: 10.1126/scitranslmed.3001943

Wounds refractory to healing—which contribute to over 72,000 amputations each year—detract substantially from the health of people with diabetes. No known effective therapies exist to treat this common cause of morbidity. One possibility is to exploit endothelial progenitor cells (EPCs), a principal cell type involved in angiogenesis; these cells, however, are known from both in vivo and ex vivo studies to be dysfunctional in diabetic individuals. So, what can be done?

Hyperglycemia, the hallmark of diabetes, leads to increased reactive oxygen species (ROS), and loss of tolerance to hyperglycemia-induced oxidative stress negatively affects EPC function. Marrotte et al. therefore tested the hypothesis that decreased activity of manganese superoxide dismutase (MnSOD), a potent antioxidant enzyme, may be a critical contributor to impaired EPC function in diabetic subjects. They isolated EPCs from type II diabetic (db/db) mice as well as control mice and studied their function in both ex vivo and in vivo assays. Specifically, they found that EPCs from diabetic mice (as compared with those from control mice) were reduced in number, exhibited decreased MnSOD expression and enzymatic activity, and demonstrated increased mitochondrial oxidative stress, impairing their functional capabilities. The authors then evaluated whether ex vivo gene therapy of EPCs would lead to improved wound healing and angiogenesis. Not only did cell therapy of diabetic wounds with EPCs accelerated wound healing, but MnSOD gene therapy also restored diabetic EPC function, and topical transplantation of MnSOD gene therapy–treated diabetic EPCs restored their ability to mediate angiogenesis and wound repair in the recipient animal. Conversely, small interfering RNA–mediated knockdown of MnSOD in normal EPCs reduced their activity in diabetic wound-healing assays, further supporting the importance of MnSOD in optimal EPC function.

In summary, Marrotte et al.’s findings in diabetic mice demonstrate that cell therapy with diabetic EPCs after their transfection ex vivo with MnSOD may be a good way to augment angiogenesis and improve wound healing in diabetic humans. Given the substantial morbidity incurred by diabetic wounds, this approach to an old problem may be welcome new blood.

E. J. Marrotte et al., Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice. J. Clin. Invest. 8 November 2010 (10.1172/JCI36858). [Full Text]

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