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.
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.
Authors: James D Kretlow; Patrick P Spicer; John A Jansen; Charles A Vacanti; F Kurtis Kasper; Antonios G Mikos Journal: Tissue Eng Part A Date: 2010-10-12 Impact factor: 3.845
Authors: D A Leonard; J M Kurtz; C Mallard; A Albritton; R Duran-Struuck; E A Farkash; R Crepeau; A Matar; B M Horner; M A Randolph; D H Sachs; C A Huang; C L Cetrulo Journal: Am J Transplant Date: 2014-01-09 Impact factor: 8.086
Authors: Krisztian Nemeth; Andrea Keane-Myers; Jared M Brown; Dean D Metcalfe; James D Gorham; Jared D Gorham; Virgilio G Bundoc; Victor G Bundoc; Marcus G Hodges; Ivett Jelinek; Satish Madala; Sarolta Karpati; Eva Mezey Journal: Proc Natl Acad Sci U S A Date: 2010-03-15 Impact factor: 11.205
Authors: David W Mathes; Billanna Hwang; Scott S Graves; James Edwards; Jeff Chang; Barry E Storer; Tiffany Butts-Miwongtum; George E Sale; Richard A Nash; Rainer Storb Journal: Transplantation Date: 2011-12-27 Impact factor: 4.939