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


CONCLUSIONS
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.
Kuo
Yur-Ren
YR
Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan. t1207816@ms22.hinet.net
Goto
Shigeru
S
Shih
Hsiang-Shun
HS
Wang
Feng-Sheng
FS
Lin
Chien-Chih
CC
Wang
Chun-Ting
CT
Huang
Eng-Yen
EY
Chen
Chao-Long
CL
Wei
Fu-Chan
FC
Zheng
Xin Xiao
XX
Lee
W P Andrew
WP
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D016572:Cyclosporine / Q000627:therapeutic use; D005269:Femur / Q000473:pathology / Q000637:transplantation; D005360:Fibula / Q000473:pathology / Q000637:transplantation; D006085:Graft Survival; D006614:Hindlimb / Q000637:transplantation*; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology; D013552:Swine; D013556:Swine, Miniature; D013601:T-Lymphocytes / Q000276:immunology; D013977:Tibia / Q000473:pathology / Q000637:transplantation; D016042:Transplantation, Heterotopic / Q000473:pathology; D014184:Transplantation, Homologous / Q000473:pathology / Q000502:physiology*
D053645:Interleukin-2 Receptor alpha Subunit; D016572:Cyclosporine