Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice
Eric J. Marrotte, … , Jeffrey S. Hakim, Alex F. Chen
Eric J. Marrotte, … , Jeffrey S. Hakim, Alex F. Chen
Published November 8, 2010
Citation Information: J Clin Invest. 2010;120(12):4207-4219. https://doi.org/10.1172/JCI36858.
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Manganese superoxide dismutase expression in endothelial progenitor cells accelerates wound healing in diabetic mice

Abstract

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.

Authors

Eric J. Marrotte, Dan-Dan Chen, Jeffrey S. Hakim, Alex F. Chen

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Figure 5

EPC therapy of diabetic wounds improved the rate of wound closure in type 2 diabetic mice.

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EPC therapy of diabetic wounds improved the rate of wound closure in typ...
The closure rate of 6-mm punch biopsies was measured every other day until day 16. Wound healing of normal db/+ mice and type 2 diabetic db/db mice represent the baseline, are the same for A–C, and represent the control groups. (A) For db/+ and db/db mice that were transplanted with 1 × 106db/+ EPCs, EPCs significantly improved the rate of wound closure in db/+ mice compared with that of db/db mice transplanted with 1 × 106db/db EPCs (*P 0.01 and #P < 0.01 vs. 1 × 106db/db EPCs, n = 10 each group). Wounds of db/+ and db/db mice transplanted with 1 × 106db/+ EPCs healed at equivalent rates (P = 0.185 vs. 1 × 106db/+ EPCs, n = 10 each group). (B) MnSOD gene therapy of EPCs prior to transplantation (1 × 106db/db-AdMnSOD EPCs) significantly improved db/db EPC ability to ameliorate wound closure versus transplantation of 1 × 106 control GFP db/db EPCs (db/db-AdGFP EPCs) (†P < 0.01 vs. 1 × 106db/db-AdGFP EPCs, n = 10 each group). (C) Transplantation of 2 × 106db/db-AdMnSOD EPCs significantly improved the rate of wound closure versus that of 2 × 106db/db-AdGFP EPCs (‡P < 0.05 vs. 2 × 106db/db-AdGFP EPCs, n = 10 each group). No difference was found in the rate of wound closure among 2 × 106db/db-AdMnSOD EPCs and 1 × 106db/+ EPCs or in db/+ mice. Transplantation of 2 × 106db/db-AdMnSOD EPCs significantly improved the rate of wound closure in db/db mice versus that of other cell therapy groups (i.e., 1 × 106db/db EPCs, 1 × 106db/db-AdMnSOD EPCs, and 1 × 106db/db-AdGFP EPCs). (D) Typical photographs of wound healing for above groups.