Mesenchymal stem cells prolong composite tissue allotransplant survival in a swine model

Yur Ren Kuo, Shigeru Goto, Hsiang Shun Shih, Feng Sheng Wang, Chien Chih Lin, Chun Ting Wang, Eng Yen Huang, Chao Long Chen, Fu Chan Wei, Xin Xiao Zheng, W. P.Andrew Lee

Research output: Contribution to journalArticle

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Abstract

BACKGROUND.: This study investigated whether mesenchymal stem cells (MSCs) combined with bone marrow transplantation (BMT), irradiation, or short-term immunosuppressant therapy could prolong composite tissue allotransplant survival in a swine hind-limb model. METHODS.: Heterotopic hind-limb transplantation was performed in outbred miniature swine. Group I (n=5) was the untreated control. Group II (n=3) received MSCs alone (given on days -1, +3, +7, +14, +21). Group III (n=6) received cyclosporine A (CsA days 0 to +28). Group IV (n=4) received preconditioning irradiation (day -1), BMT (day +1), and CsA (days 0 to +28). Group V (n=5) received irradiation (day -1), BMT (day +1), CsA (days 0 to +28), and MSCs (days +1, +7,+14). The expression and localization of CD4/CD25 T cells and MSCs were assessed using flow cytometry and immunohistochemistry. RESULTS.: The allografts survival with MSCs alone revealed a significant prolongation, when compared with the controls (P=0.02). Allografts with CsA treatment exhibited delayed rejection. Irradiation and BMT-CsA treatment revealed no significant allograft survival benefit when compared with the CsA treatment group, but graft-versus-host disease (GVHD) was evident. However, combination of MSCs-BMT-CsA treatment demonstrated significant prolongation of allograft survival (>200 days, P<0.001) and no signs of GVHD with the lowest degree of rejection in the allo-skin and interstitial muscle layers. The CD4/CD25 regulatory-like T-cell expression in the circulating blood and allo-skin significantly increased in the MSC-BMT-CsA group. Examination of bromodeoxyuridine-labeled MSCs revealed donor MSC engraftment into the recipient and donor skin and the recipient liver parenchymal tissue. CONCLUSION.: These results suggested that the regulatory activity of MSCs on T cells and GVHD might contribute to significant prolongation of composite tissue allotransplant survival in the MSC-BMT-CsA treatment.

Original languageEnglish (US)
Pages (from-to)1769-1777
Number of pages9
JournalTransplantation
Volume87
Issue number12
DOIs
StatePublished - Jun 27 2009
Externally publishedYes

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Tissue Survival
Mesenchymal Stromal Cells
Swine
Bone Marrow Transplantation
Allografts
Graft vs Host Disease
Skin
Therapeutics
Extremities
T-Lymphocytes
Miniature Swine
Regulatory T-Lymphocytes
Bromodeoxyuridine
Immunosuppressive Agents
Cyclosporine
Flow Cytometry
Transplantation
Immunohistochemistry

Keywords

  • Composite tissue allotransplant
  • Mesenchymal stem cells

ASJC Scopus subject areas

  • Transplantation

Cite this

Mesenchymal stem cells prolong composite tissue allotransplant survival in a swine model. / Kuo, Yur Ren; Goto, Shigeru; Shih, Hsiang Shun; Wang, Feng Sheng; Lin, Chien Chih; Wang, Chun Ting; Huang, Eng Yen; Chen, Chao Long; Wei, Fu Chan; Zheng, Xin Xiao; Lee, W. P.Andrew.

In: Transplantation, Vol. 87, No. 12, 27.06.2009, p. 1769-1777.

Research output: Contribution to journalArticle

Kuo, YR, Goto, S, Shih, HS, Wang, FS, Lin, CC, Wang, CT, Huang, EY, Chen, CL, Wei, FC, Zheng, XX & Lee, WPA 2009, 'Mesenchymal stem cells prolong composite tissue allotransplant survival in a swine model', Transplantation, vol. 87, no. 12, pp. 1769-1777. https://doi.org/10.1097/TP.0b013e3181a664f1
Kuo, Yur Ren ; Goto, Shigeru ; Shih, Hsiang Shun ; Wang, Feng Sheng ; Lin, Chien Chih ; Wang, Chun Ting ; Huang, Eng Yen ; Chen, Chao Long ; Wei, Fu Chan ; Zheng, Xin Xiao ; Lee, W. P.Andrew. / Mesenchymal stem cells prolong composite tissue allotransplant survival in a swine model. In: Transplantation. 2009 ; Vol. 87, No. 12. pp. 1769-1777.
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abstract = "BACKGROUND.: This study investigated whether mesenchymal stem cells (MSCs) combined with bone marrow transplantation (BMT), irradiation, or short-term immunosuppressant therapy could prolong composite tissue allotransplant survival in a swine hind-limb model. METHODS.: Heterotopic hind-limb transplantation was performed in outbred miniature swine. Group I (n=5) was the untreated control. Group II (n=3) received MSCs alone (given on days -1, +3, +7, +14, +21). Group III (n=6) received cyclosporine A (CsA days 0 to +28). Group IV (n=4) received preconditioning irradiation (day -1), BMT (day +1), and CsA (days 0 to +28). Group V (n=5) received irradiation (day -1), BMT (day +1), CsA (days 0 to +28), and MSCs (days +1, +7,+14). The expression and localization of CD4/CD25 T cells and MSCs were assessed using flow cytometry and immunohistochemistry. RESULTS.: The allografts survival with MSCs alone revealed a significant prolongation, when compared with the controls (P=0.02). Allografts with CsA treatment exhibited delayed rejection. Irradiation and BMT-CsA treatment revealed no significant allograft survival benefit when compared with the CsA treatment group, but graft-versus-host disease (GVHD) was evident. However, combination of MSCs-BMT-CsA treatment demonstrated significant prolongation of allograft survival (>200 days, P<0.001) and no signs of GVHD with the lowest degree of rejection in the allo-skin and interstitial muscle layers. The CD4/CD25 regulatory-like T-cell expression in the circulating blood and allo-skin significantly increased in the MSC-BMT-CsA group. Examination of bromodeoxyuridine-labeled MSCs revealed donor MSC engraftment into the recipient and donor skin and the recipient liver parenchymal tissue. CONCLUSION.: These results suggested that the regulatory activity of MSCs on T cells and GVHD might contribute to significant prolongation of composite tissue allotransplant survival in the MSC-BMT-CsA treatment.",
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AU - Shih, Hsiang Shun

AU - Wang, Feng Sheng

AU - Lin, Chien Chih

AU - Wang, Chun Ting

AU - Huang, Eng Yen

AU - Chen, Chao Long

AU - Wei, Fu Chan

AU - Zheng, Xin Xiao

AU - Lee, W. P.Andrew

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N2 - BACKGROUND.: This study investigated whether mesenchymal stem cells (MSCs) combined with bone marrow transplantation (BMT), irradiation, or short-term immunosuppressant therapy could prolong composite tissue allotransplant survival in a swine hind-limb model. METHODS.: Heterotopic hind-limb transplantation was performed in outbred miniature swine. Group I (n=5) was the untreated control. Group II (n=3) received MSCs alone (given on days -1, +3, +7, +14, +21). Group III (n=6) received cyclosporine A (CsA days 0 to +28). Group IV (n=4) received preconditioning irradiation (day -1), BMT (day +1), and CsA (days 0 to +28). Group V (n=5) received irradiation (day -1), BMT (day +1), CsA (days 0 to +28), and MSCs (days +1, +7,+14). The expression and localization of CD4/CD25 T cells and MSCs were assessed using flow cytometry and immunohistochemistry. RESULTS.: The allografts survival with MSCs alone revealed a significant prolongation, when compared with the controls (P=0.02). Allografts with CsA treatment exhibited delayed rejection. Irradiation and BMT-CsA treatment revealed no significant allograft survival benefit when compared with the CsA treatment group, but graft-versus-host disease (GVHD) was evident. However, combination of MSCs-BMT-CsA treatment demonstrated significant prolongation of allograft survival (>200 days, P<0.001) and no signs of GVHD with the lowest degree of rejection in the allo-skin and interstitial muscle layers. The CD4/CD25 regulatory-like T-cell expression in the circulating blood and allo-skin significantly increased in the MSC-BMT-CsA group. Examination of bromodeoxyuridine-labeled MSCs revealed donor MSC engraftment into the recipient and donor skin and the recipient liver parenchymal tissue. CONCLUSION.: These results suggested that the regulatory activity of MSCs on T cells and GVHD might contribute to significant prolongation of composite tissue allotransplant survival in the MSC-BMT-CsA treatment.

AB - BACKGROUND.: This study investigated whether mesenchymal stem cells (MSCs) combined with bone marrow transplantation (BMT), irradiation, or short-term immunosuppressant therapy could prolong composite tissue allotransplant survival in a swine hind-limb model. METHODS.: Heterotopic hind-limb transplantation was performed in outbred miniature swine. Group I (n=5) was the untreated control. Group II (n=3) received MSCs alone (given on days -1, +3, +7, +14, +21). Group III (n=6) received cyclosporine A (CsA days 0 to +28). Group IV (n=4) received preconditioning irradiation (day -1), BMT (day +1), and CsA (days 0 to +28). Group V (n=5) received irradiation (day -1), BMT (day +1), CsA (days 0 to +28), and MSCs (days +1, +7,+14). The expression and localization of CD4/CD25 T cells and MSCs were assessed using flow cytometry and immunohistochemistry. RESULTS.: The allografts survival with MSCs alone revealed a significant prolongation, when compared with the controls (P=0.02). Allografts with CsA treatment exhibited delayed rejection. Irradiation and BMT-CsA treatment revealed no significant allograft survival benefit when compared with the CsA treatment group, but graft-versus-host disease (GVHD) was evident. However, combination of MSCs-BMT-CsA treatment demonstrated significant prolongation of allograft survival (>200 days, P<0.001) and no signs of GVHD with the lowest degree of rejection in the allo-skin and interstitial muscle layers. The CD4/CD25 regulatory-like T-cell expression in the circulating blood and allo-skin significantly increased in the MSC-BMT-CsA group. Examination of bromodeoxyuridine-labeled MSCs revealed donor MSC engraftment into the recipient and donor skin and the recipient liver parenchymal tissue. CONCLUSION.: These results suggested that the regulatory activity of MSCs on T cells and GVHD might contribute to significant prolongation of composite tissue allotransplant survival in the MSC-BMT-CsA treatment.

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