title: Transforming growth factor-β-Expressing Mesenchymal Stem Cells Induce Local Tolerance in a Rat Liver Transplantation Model of Acute Rejection.
abstract: Acute rejection is commonly encountered for long-term survival in liver transplant (LT) recipients and may impact their long-term survival if rejection is severe or recurrent. The aim of this study is to examine the therapeutic potential of transforming growth factor (TGF-β)-overexpressing mesenchymal stem cells (MSCs) in inducing a local immunosuppression in liver grafts after transplantation. MSCs were transduced with a lentiviral vector expressing the human TGF-β1 gene; TGF-β1-overexpressing MSCs (designated as TGF/MSCs) were then transfused into the liver grafts via the portal vein of a rat LT model of acute rejection. Rejection severity was assessed by clinical and histologic analysis. The immunity suppression effects and mechanism of TGF/MSCs were tested, focusing on their ability to induce generation of regulatory T cells (Tregs) in the liver grafts. Our findings demonstrate that transfusion of TGF/MSCs prevented rejection, reduced mortality, and improved survival of rats after LT. The therapeutic effects were associated with the immunosuppressive effects of MSCs and TGF-β1. Their reciprocal effects on Tregs induction and function resulted in more CD4 + Foxp3 + Helios- induced Tregs, fewer Th17 cells, and improved immunosuppressive effects in local liver grafts. Thus, TGF/MSCs can induce a local immunosuppressive effect in liver grafts after transplantation. The immunomodulatory activity of TGF-β1 modified MSCs may be a gateway to new therapeutic approaches to prevent organ rejection in clinical transplantation. Stem Cells 2016;34:2681-2692.
authors.affiliation: Liver Transplantation Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.|Digestive Medical Center, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Jincao
authors.initials: J
authors.lastname: Tang
authors.affiliation: Liver Transplantation Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Renjie
authors.initials: R
authors.lastname: Yang
authors.affiliation: Liver Transplantation Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.|Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Lv
authors.affiliation: Liver Transplantation Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.|Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province, China.
authors.forename: Aihua
authors.initials: A
authors.lastname: Yao
authors.affiliation: Liver Transplantation Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.|Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province, China.
authors.forename: Liyong
authors.initials: L
authors.lastname: Pu
authors.affiliation: Liver Transplantation Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.|Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province, China.
authors.forename: Aihong
authors.initials: A
authors.lastname: Yin
authors.affiliation: Liver Transplantation Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.|Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province, China.
authors.forename: Xiangcheng
authors.initials: X
authors.lastname: Li
authors.affiliation: Liver Transplantation Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.|Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Surgery, Division of Experimental Surgery, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Nyberg
authors.affiliation: Liver Transplantation Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.|Key Laboratory of Living Donor Liver Transplantation, Ministry of Public Health, Nanjing, Jiangsu Province, China.
authors.forename: Xuehao
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D005822:Genetic Vectors / Q000737:chemistry / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000276:immunology; D016130:Immunophenotyping; D016086:Lentivirus / Q000235:genetics / Q000378:metabolism; D016031:Liver Transplantation; D018655:Lymphocyte Count; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D051381:Rats; D016019:Survival Analysis; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology / Q000473:pathology; D014161:Transduction, Genetic; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000276:immunology; D023001:Transplantation Tolerance
chemical_list: D015704:CD4 Antigens; D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1; D051740:Ikaros Transcription Factor
keywords: Cellular therapy; Immunosuppression; Liver; Marrow stromal stem cells; Mesenchymal stem cells; Rat model; Transforming growth factor-β; Transplantation tolerance