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Indoleamine 2,3-dioxgenase-transfected mesenchymal stem cells suppress heart allograft rejection by increasing the production and activity of dendritic cells and regulatory T cells
  1. Ji-Gang He1,
  2. Bei-Bei Li1,
  3. Liang Zhou2,
  4. Dan Yan3,
  5. Qiao-Li Xie1,
  6. Wei Zhao1
  1. 1 Department of Cardiac and Vascular Surgery, First People's Hospital of Yunnan Province, Kunming, China
  2. 2 Department of Cardiology, First People's Hospital of Yunnan Province, Kunming, China
  3. 3 Intensive Care Unit, First People's Hospital of Yunnan Province, Kunming, China
  1. Correspondence to Dr Wei Zhao, Department of Cardiac and Vascular Surgery, First People's Hospital of Yunnan Province, Kunming 650032, China; jiganghe999{at}163.com

Abstract

Expression of indoleamine 2,3-dioxygenase (IDO) in mesenchymal stem cells (MSC) is thought to contribute to MSC-mediated immunosuppression. A lentiviral-based transgenic system was used to generate bone marrow stem cells (BMSC) which stably expressed IDO (IDO-BMSCs). Coculture of IDO-BMSCs with dendritic cells (DC) or T cells was used to evaluate the immunomodulatory effect of IDO-BMSCs. A heterotopic heart transplant model in rats was used to evaluate allograft rejection after IDO-BMSC treatment. Mechanisms of IDO-BMSC-mediated immunosuppression were investigated by evaluating levels of proinflammatory and anti-inflammatory cytokines, and production of Tregs. A significant decrease in DC marker-positive cells and a significant increase in Tregs were observed in IDO-BMSC cocultured. Treatment of transplanted rats with IDO-BMSCs was associated with significantly prolonged graft survival. Compared with the control groups, transplanted animals treated with IDO-BMSCs had a (1) significantly higher ejection fraction and fractional shortening, (2) significantly lower expression of CD86, CD80, and MHCII, and significantly higher expression in CD274, and Tregs, and (3) significantly higher levels of interleukin-10 (IL-10), transforming growth factor beta-1 (TGF-β1), TGF-β2, and TGF-β3, and significantly lower levels of IL-2 and interferon gamma. Our results expand our understanding of the molecular mechanisms underlying suppression of heart allograft rejection via IDO-expressing BMSCs.

  • stem cells
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Footnotes

  • Contributors JGH: guarantor of integrity of the entire study, study concepts, study design, definition of intellectual content, literature research, clinical studies, experimental studies, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript editing, manuscript review. BBL: study design, definition of intellectual content, literature research, clinical studies, experimental studies. LZ: definition of intellectual content, literature research, clinical studies, experimental studies. DY: literature research, clinical studies, experimental studies, data acquisition, data analysis, statistical analysis, manuscript preparation, manuscript editing. QLX: literature research, clinical studies, experimental studies, data acquisition, data analysis, manuscript editing. WZ: guarantor of integrity of the entire study, study concepts, study design, definition of intellectual content, experimental studies, data analysis, manuscript review.

  • Funding This work was supported by the National Natural Science Foundation of China (No 81460073), the Special Fund for the Basic Application Research of Yunnan Provincial Science and Technology Department and Kunming Medical University (No 2014FB089; No 2019FE(-120)), and the Department of Education Fund for Scientific Research Project of Yunnan Provincial (No 2015Z051). This study was also supported by the 58th batch funds of China Postdoctoral Science Foundation (No 2015M582764XB) and the 2015 Scientific Research Project of Chengdu Medical College (CYZ15-18).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement No data are available.

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