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Prolongation of Composite Tissue Allotransplant Survival by Treatment with Bone Marrow Mesenchymal Stem Cells Is Correlated with T-Cell Regulation in a Swine Hind-Limb Model

Kuo, Yur-Ren M.D., Ph.D.; Chen, Chien-Chang M.D.; Shih, Hsiang-Shun M.D.; Goto, Shigeru M.D., Ph.D.; Huang, Chong-Wei M.S.; Wang, Chun-Ting B.S.; Chen, Chao-Long M.D.; Wei, Fu-Chan M.D.

Plastic and Reconstructive Surgery: February 2011 - Volume 127 - Issue 2 - p 569-579
doi: 10.1097/PRS.0b013e318200a92c
Experimental: Original Articles

Background: Recently published reports indicate that treatment with mesenchymal stem cells combined with bone marrow transplantation could prolong survival after composite tissue allotransplantation. This study investigated whether bone marrow mesenchymal stem cells combined with irradiation and short-term immunosuppressant therapy, but without bone marrow transplantation, could prolong composite tissue allotransplantation survival. Correlation with regulatory T-cell populations was also evaluated in a swine hind-limb model.

Methods: Heterotopic hind-limb transplantation was performed in outbred miniature swine. Group I (n = 4) was the untreated control. Group II (n = 3) received mesenchymal stem cells alone (on days –1, 3, 7, 14, and 21). Group III (n = 5) received cyclosporine A (on days 0 through 28). Group IV (n = 3) received irradiation (on day –1), mesenchymal stem cells (on days 1, 7, 14, and 21), and cyclosporine A (on days 0 to 28). Swine viability and signs of allograft rejection were monitored postoperatively. Histopathologic changes in allografts were examined. The expression and localization of CD4+/CD25+ and CD4+/FoxP3+ T cells were assessed using flow cytometry and immunohistochemistry.

Results: Treatment with mesenchymal stem cells along with irradiation and cyclosporine A resulted in significant increases in allograft survival as compared with other groups (>120 days; p = 0.018). Histologic examination revealed the lowest degree of rejection in grafted skin and interstitial muscle layers in the mesenchymal stem cell/irradiation/cyclosporine A group. Flow cytometric analysis revealed a significant increase in the percentage of CD4+/CD25+ and CD4+/FoxP3+ T cells in both the blood and graft in the mesenchymal stem cell/irradiation/cyclosporine A group.

Conclusion: These results suggest that prolonged survival after composite tissue allotransplantation induced by treatment with mesenchymal stem cells combined with irradiation/cyclosporine A is correlated with regulatory T cells.

Kaohsiung, Taiwan

From the Department of Plastic and Reconstructive Surgery, Department of Medical Research, Liver Transplantation Program, and Department of Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine.

Received for publication February 12, 2010; accepted July 21, 2010.

The first two authors contributed equally to this work and should be considered co-first authors.

Presented at the 54th Annual Meeting of the Plastic Surgery Research Council, in Pittsburgh, Pennsylvania, May 28 through 31, 2009, and the 25th Annual Meeting of the American Society for Reconstructive Microsurgery, in Boca Raton, Florida, January 9 through 12, 2010.

Disclosure: The authors have no financial interest in any of the products or devices mentioned in this article.

Yur-Ren Kuo, M.D., Ph.D.; Department of Plastic and Reconstructive Surgery; Chang Gung Memorial Hospital; Kaohsiung Medical Center; Chang Gung University College of Medicine; 123 Ta-Pei Road; Niao-Sung Hsiang; Kaohsiung 83305, Taiwan;

©2011American Society of Plastic Surgeons