Abstract
We examined whether haem oxygenase-1 (HO-1) could enhance the immunosuppressive effects of bone marrow mesenchymal stem cells (BMMSCs) on the rejection of transplanted liver allografts in rats. The animals were divided into three groups: the normal saline (NS) group, BMMSC group and HO-1/BMMSCs group. In vitro, the extraction, culture and HO-1 transfection of BMMSCs were performed. Mixed lymphocyte response (MLR) analysis of HO-1/BMMSCs efficacy was performed. The rejection model of orthotopic liver transplantation in rats was established when BMMSCs and HO-1/BMMSCs were transfused via the portal vein. To reduce research bias, we established an isogenic Liver transplantation model of (LEW → LEW) and (BN → BN), which can achieve tolerance. Changes in histopathology and liver function in the transplanted liver and changes in regulatory T cell (Tregs), natural killer (NK) cells and cytokines after transplantation were observed in the different groups. The severe acute rejection after liver transplantation on postoperative Day 10 was observed in the NS group. The BMMSC group showed strong protective effects against rejection within the first 10 days after transplantation, while HO-1/BMMSCs showed stronger effects on rejection than BMMSCs alone. In addition, the activity of natural killer (NK) cells decreased significantly, the levels of regulatory T cells (Tregs), interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) increased significantly and the levels of interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-17 (IL-17), interleukin-23 (IL-23), tumour necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) decreased significantly in the HO-1/BMMSC group compared with the BMMSC group. HO-1/BMMSCs showed better immunosuppressive effects after liver transplantation than the other treatments. Our findings reveal that HO-1 can enhance the effects of BMMSCs on inhibiting acute rejection in orthotopic liver transplantation in rats.
Highlights
We examined whether haem oxygenase-1 (HO-1) could enhance the immunosuppressive effects of bone marrow mesenchymal stem cells (BMMSCs) on the rejection of transplanted liver allografts in rats
The cells after being passaged were long, fusiform and arranged in a vortex or chrysanthemum shape with typical BMMSCs morphological features (Fig. 1A). 2 The cells could differentiate into adipocytes and osteoblasts (Fig. 1C). 3 Analysis of cell surface markers showed the expression of C D29+CD34−, CD90+CD45− and R T1A+RT1B− in 99.5%,99.8% and 98.5% of cells, respectively (Fig. 1G–I)
BMMSCs were infected with recombinant adenovirus expressing HO-1, and the GFP gene was used as a reference
Summary
Culture and identification of BN rat BMMSCs. Rat BMMSCs were successfully cultured and expanded in vitro. 1 The cells adherently grew. Of rats in the HO/BMMSC group remained normal until 20 days after surgery, and their body weight gradually increased. Statistical analysis showed that the HO-1/BMMSC group had further increased Treg levels compared with the BMMSC group, especially on the 10th day. The ELISA results showed that the expression levels of cytokines related to anti-inflammatory effects or Treg differentiation, such as IL-10 and TGF-β, were further increased in the HO-1/BMMSC group compared with the NS group and BMMSC group. The activity of NK cells in the HO-1/BMMSC group did not significantly increase during the observation period but only fluctuated around normal levels. Statistical analysis showed that NK cell activity was further reduced to near normal levels in the HO-1/BMMSC group, and the difference was statistically significant (Fig. 6). The positive effect of HO-1/BMMSCs was reflected in the allogeneic LT from the syngraft model
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