Mesenchymal stem cells improve the outcomes of liver recipients via regulating CD4+ T helper cytokines in rats.
BACKGROUND
Bone marrow mesenchymal stem cells (BMMSCs) exert immunosuppressive activities in transplantation. This study aimed to determine whether BMMSCs reduce acute rejection and improve outcomes of liver transplantation in rats.


METHODS
Orthotopic liver transplantation from Lewis to Brown Norway rats was performed, which was followed by the infusion of BMMSCs through the penile superficial dorsal vein. Normal saline infusion was used as a control. Animals were sacrificed at 0, 24, 72, or 168 hours after BMMSCs infusion. Liver grafts, and recipient serum and spleen tissues were obtained. Histopathology, apoptosis, serum liver enzymes, serum cytokines, and circulating regulatory T (Treg), Th1, Th2 and Th17 cells were assessed at each time point.


RESULTS
BMMSCs significantly attenuated acute rejection and improved the survival rate of allogeneic liver transplantation recipients. Liver enzymes and liver apoptosis were significantly alleviated. The levels of the Th1/Th2 ratio-associated cytokines such as IL-2 and IFN-gamma were significantly reduced and IL-10 was significantly increased. The levels of the Th17/Tregs axis-associated cytokines such as IL-6, IL-17, IL-23, and TNF-alpha were significantly reduced, whereas TGF-beta concentration was significantly increased. Moreover, flow cytometry analysis showed that the infusion of BMMSCs significantly increased Th2 and Treg cells and decreased Th1 and Th17 cells.


CONCLUSIONS
BMMSCs had immunomodulatory effects, attenuated acute rejection and improved outcomes of allogeneic liver transplantation in rats by regulating the levels of cytokines associated with Th1/Th2 and Th17/Treg ratios.
Department of Organ Transplantation, Tianjin First Central Hospital, Tianjin 300192, China. hlsong26@163.com.
Yang
Y
Yang
Zhong-Yang
ZY
Shen
Bin
B
Wu
Ming-Li
ML
Yin
Bo-Ya
BY
Zhang
Hong-Li
HL
Song
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000097:blood; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood*; D006084:Graft Rejection / Q000097:blood / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D006085:Graft Survival; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D016031:Liver Transplantation / Q000009:adverse effects / Q000379:methods*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D023421:Models, Animal; D010641:Phenotype; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
D015415:Biomarkers; D016207:Cytokines