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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Research Article Dermatology

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 8

Typical photographs of CD31 staining on day 6 of wound healing.

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In vivo integration of transplanted EPCs on day 6 of wound healing. At t...
(A and B) db/+ mice, (C and D) db/db mice, and (E and F) db/db mice, with EPC therapy of 1 × 106db/+ EPCs, (G and H) db/db EPCs, (I and J) db/db-AdMnSOD EPCs, (K and L) db/db-AdGFP EPCs, (M and N) 2 × 106db/db-AdMnSOD EPCs, and (O and P) 2 × 106db/db-AdGFP EPCs. Green arrows point to CD31-positive capillaries. (Q and R) Typical photographs of CD34 staining on day 6 of wound healing in db/+ mice. Green arrows point to CD34-positive capillaries. (S and T) Typical photographs of vWF staining on day 6 of wound healing in db/+ mice. Green arrows point to vWF-positive capillaries. Boxed regions are shown at higher magnification to the right. Statistic analyses are shown in Figure 7B. W, wound; Dm, dermis; E, epidermis. Scale bar: 500 μm (A, C, E, G, I, K, M, O, Q, and S); 100 μm (B, D, F, H, J, L, N, P, R, and T). Original magnification, ×40 (A, C, E, G, I, K, M, O, Q, and S); ×200 (B, D, F, H, J, L, N, P, R, and T).