Improvement of Liver Transplantation Outcome by Heme Oxygenase‐1‐Transduced Bone Marrow Mesenchymal Stem Cells in Rats

Abstract

Bone marrow mesenchymal stem cells (BMMSCs) exert immunosuppressive activity in transplantation, and heme oxygenase-1 (HO-1) enhances their immunomodulatory effects. The aim of this study was to determine whether HO-1-transduced BMMSCs (HO-1/MSCs) improve rat liver transplantation (LTx) outcomes. Orthotopic LTx rejection models were treated with HO-1/MSCs, BMMSCs, HO-1, or normal saline, respectively. Our results showed a significant improvement in survival rates in the HO-1/BMMSCs group compared to the control groups. At all time points, liver function marker levels in the HO-1/MSCs group were significantly lower than in the other three groups; on POD 1, 7, and 14, the degree of rejection and apoptotic cells was significantly less in the HO-1/MSCs group than in the other three groups. Interleukin- (IL-) 10 and transforming growth factor-β levels were significantly increased, while IL-2, IL-6, IL-17, IL-23, tumor necrosis factor-α, and interferon-γ levels were significantly decreased in the HO-1/MSCs group when compared to the other groups. Splenocyte Tregs were significantly increased by HO-1/MSCs compared with controls on POD 3, 5, 7, 10, 14, and 28. Summarily, we provide evidence that HO-1/MSCs improved allogeneic LTx outcomes by attenuating inflammatory responses and acute cellular rejection, as well as enhanced immunomodulatory effects compared with BMMSCs.

Protective effects of heme oxygenase-1-transduced bone marrow-derived mesenchymal stem cells on reduced-size liver transplantation: Role of autophagy regulated by the ERK/mTOR signaling pathway

“…After cutting off both ends of the epiphyseal, the marrow cavity was rinsed by DMEM/F12 (Gibco, Thermo Fisher Scientific, Inc., Waltham, MA, USA) containing 10% fetal bovine serum (FBS). Red blood cells were lysed using 0.1 mol/l NH 4 Cl, and the remaining cells were washed, resuspended, and cultured 1×10 6 /T75 culture flask at 37°C with 5% CO 2 in Dulbecco's modified Eagle's medium (DMEM)/F12 containing 100 U/ml penicillin, 100 mg/ml streptomycin and 15% FBS ( 13 ). The well-grown third-passage BM-MSCs were resuspended at 1×10 6 /ml and then labeled with antibodies against CD29 (1:80, PE, 102207), CD90 (1:200, FITC, 202503), CD45 (1:80, PE, 202207), RT1A (1:80, PE, 205208), RT1B (1:200, FITC, 205305) (both from BioLegend, Inc., San Diego, CA, USA) and CD34 (1:5, FITC, sc-7324; Santa Cruz Biotechnology, Inc., Dallas, TX, USA) for 30 min for flow cytometric analysis (BD FACSAria III; BD Biosciences, Franklin Lakes, NJ, USA) of the expression of cell surface markers.…”

“…HO-1 can increase the activity and prolong the duration of BM-MSCs ( 11 ). Previous studies of the authors have demonstrated that HO-1-transduced BM-MSCs (HO-1/BM-MSCs) may protect the transplanted liver by participating in the regulation of transplantation immunity and repair of the damaged liver tissue ( 12 , 13 ). However, the mechanism of this protective effect remains unknown.…”

Effect of heme oxygenase‐1 transduced bone marrow mesenchymal stem cells on damaged intestinal epithelial cells in vitro

“…Treatment with both HO‐1 and MSCs relieved inflammation, while which HO‐MSCs showed the most significant effects (Zeng et al, ). HO‐MSCs may therefore reduce intestinal epithelial injury by inhibiting the release of inflammatory cytokines such as IL‐2, IL‐6, and IFN‐γ, and promoting the release of anti‐inflammatory cytokine IL‐10 (Wu et al, ), leading to increased expression of tight junction proteins and proliferation of intestinal epithelium (Zhang et al, ). HO‐MSCs regulated the expression of cytokines in Caco2 cells, which might be related to the enhanced transforming ability and antioxidant effects of MSCs after Ad‐HO transduction (Vanella et al, ; Zeng et al, ; Hamedi‐Asl et al, ; Vanella et al, ), and both the activity and duration of action were enhanced.…”

Mesenchymal stromal cells promote liver regeneration through regulation of immune cells

“…Foxp3-overexpressing MSCs generated a state of Treg-dependent tolerance and induced donor-specific allograft tolerance in a contact-dependent mechanism [105]. Transplantation of heme oxygenase (HO)-1-overexpressing MSCs significantly decreased the rejection rate while increasing the survival time of LT rats by increasing the levels of peripheral Tregs and decreasing the levels of NK cells in liver tissue [106,107]. Furthermore, overexpression of HO-1 or IL-10 in MSCs significantly increased the levels of anti-inflammatory cytokines (IL-10 and TGF-β) and decreased the levels of proinflammatory cytokines (IL-2, IL-6, IL-17, IL-23, TNF-α, and IFN-γ) in LT recipients [106][107][108].…”