Journal
STEM CELLS
Volume 34, Issue 11, Pages 2681-2692Publisher
WILEY
DOI: 10.1002/stem.2437
Keywords
Immunosuppression; Rat model; Cellular therapy; Transforming growth factor-beta; Liver; Transplantation tolerance; Marrow stromal stem cells; Mesenchymal stem cells
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Funding
- National Natural Science Foundation of China [81570565]
- Jiangsu Province's Outstanding Medical Academic key program [RC2011067]
- Jiangsu Six-type Top Talents Program [2012-WS-111]
- Jiangsu Provincial Special Program of Medical Science [BL2012010]
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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-beta)-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-beta 1 gene; TGF-beta 1-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-beta 1. 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-beta 1 modified MSCs may be a gateway to new therapeutic approaches to prevent organ rejection in clinical transplantation.
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