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The Effects of Flap Ischemia on Normal and Diabetic Progenitor Cell Function

Tanaka, Rica M.D.; Wada, Mika M.D., Ph.D.; Kwon, Sang Mo Ph.D.; Masuda, Haruchika M.D., Ph.D.; Carr, Jacquelyn B.A.; Ito, Rie B.S.; Miyasaka, Muneo M.D., Ph.D.; Warren, Stephen M. M.D.; Asahara, Takayuki M.D., Ph.D.; Tepper, Oren M. M.D.

Plastic and Reconstructive Surgery: June 2008 - Volume 121 - Issue 6 - p 1929-1942
doi: 10.1097/PRS.0b013e3181715218
Experimental: Original Articles

Background: Endothelial progenitor cells play an important role in neovascularization of ischemic flaps, a process that is significantly impaired in diabetes. This is the first investigation into the effects of flap ischemia on circulating and bone marrow–derived endothelial progenitor cells. Potential mechanisms for impaired vasculogenesis in diabetes are also investigated.

Methods: Circulating and bone marrow–derived endothelial progenitor cells were isolated from wild-type (n = 24) and diabetic mice (n = 24) with ischemic flaps (days 0, 1, 3, and 7). The number and vasculogenic function of primitive and definitive endothelial progenitor cells were determined by fluorescence-activated cell sorting analysis, culture assay, and vasculogenic colony-forming assay.

Results: Ischemia mobilized endothelial progenitor cells (25 ± 0.5 cells per high-power field at day 7 versus 9.0 ± 0.6 cells per high-power field, p < 0.01) and enhanced the vasculogenic potential of circulating primitive endothelial progenitor cells (23 ± 3.2 at day 3 versus 14 ± 0.8, p < 0.01) relative to baseline. In the bone marrow, endothelial progenitor cell number and vasculogenic potential peaked at day 3 (2.1 ± 0.3 × 105 cells versus 1.3 ± 0.1 × 105 cells, p < 0.05; 36 ± 1.9 versus 27 ± 1.6, p < 0.05, respectively). In diabetes, circulating endothelial progenitor cell mobilization (5.8 ± 0.4 cells per high-power field versus 9.0 ± 0.6 cells per high-power field, p < 0.01) and vasculogenic potential (36 ± 1.7 versus 43 ± 2.6, p < 0.05) were impaired relative to the wild-type animals. Bone marrow–derived endothelial progenitor cell number was normal in diabetic animals, but the vasculogenic potential of these cells was significantly impaired (5.7 ± 0.8 day 1 versus 13.4 ± 2.5, p < 0.05).

Conclusions: Flap ischemia induces phenotypic changes in bone marrow–derived endothelial progenitor cells that subsequently traffic through the circulation. The vasculogenic potential of endothelial progenitor cells at various stages of differentiation is impaired in diabetes and thus may account for impaired ischemia-induced vasculogenesis observed clinically.

Tokyo, Japan; and New York, N.Y.

From the Division of Regenerative Medicine, Department of Basic Clinical Science, and the Department of Plastic Surgery, Tokai University School of Medicine, and the Institute of Reconstructive Plastic Surgery, New York University School of Medicine.

Received for publication July 15, 2007; accepted October 17, 2007.

Disclosure: None of the authors has a financial interest in any of the products or materials presented in this article.

Oren M. Tepper, M.D., Institute of Reconstructive Plastic Surgery, New York University School of Medicine, 550 First Avenue, TH-169, New York, N.Y. 10016,

©2008American Society of Plastic Surgeons