RETRACTED ARTICLE: Heme oxygenase-1-modified bone marrow mesenchymal stem cells combined with normothermic machine perfusion to protect donation after circulatory death liver grafts

Abstract

Background: Donation after circulatory death (DCD) liver grafts have a poor prognosis after transplantation. We investigated whether the outcome of DCD donor organs can be improved by heme oxygenase 1 (HO-1)-modified bone marrow-derived mesenchymal stem cells (BMMSCs) combined with normothermic machine perfusion (NMP), and explored its underlying mechanisms. Methods: BMMSCs were isolated, cultured, and transduced with the HO-1 gene. An NMP system was established. DCD rat livers were obtained, preserved by different methods, and the recipients were divided into 5 groups: sham operation, static cold storage (SCS), NMP, BMMSCs combined with NMP, and HO-1/BMMSCs combined with NMP (HBP) groups. Rats were sacrificed at 1, 7, and 14 days after surgery; their blood and liver tissue samples were collected; and liver enzyme and cytokine levels, liver histology, high-mobility group box 1 (HMGB1) levels in monocytes and liver tissues, and expression of Toll-like receptor 4 (TLR4) pathway-related molecules were evaluated. Results: After liver transplantation, the SCS group showed significantly increased transaminase levels, liver tissue damage, and shorter survival time. The HBP group showed lower transaminase levels, intact liver morphology, prolonged survival time, and decreased serum and liver proinflammatory cytokine levels. In the NMP and SCS groups, HMGB1 expression in the serum, monocytes, and liver tissues and TLR4 pathway-related molecule expression were significantly decreased. Conclusions: HO-1/BMMSCs combined with NMP exerted protective effects on DCD donor liver and significantly improved recipient prognosis. The effect of HO-1/BMMSCs was greater than that of BMMSCs and was mediated via HMGB1 expression and TLR4 pathway inhibition.

Combination of mesenchymal stromal cells and machine perfusion is a novel strategy for organ preservation in solid organ transplantation

“…After 4 h of ex vivo perfusion, the liver was transplanted. Although the BM-MSC group had already demonstrated beneficial effects on survival time, liver function, proinflammatory cytokines, high-mobility group box 1 (HMGB1) expression, TLR4/NF-κB pathway inhibition and morphological changes compared with the control group, the HO-1/BM-MSCs group showed additional benefits (Cao et al 2020 ).…”

HO-1/Bmmscs Perfusion Using a Normothermic Machine Perfusion System Reduces the Acute Rejection of DCD Liver Transplantation by Regulating NKT Cell Co-Inhibitory Receptors

“…BMMSCs were prepared in accordance with our previous methods [16,17]. Brie y, the femurs and tibias were removed under aseptic conditions after the rats had been executed and sterilized, and BMMSCs were extracted using a whole bone marrow apposition screening method, and perfused or transfected with HO-1 after culturing to the third generation.…”

“…The donor liver was perfused with portal vein, and the perfusion temperature was maintained at 36°C − 38°C. The main components of the perfusion uid consist of 20% fetal bovine serum (FBS, Biowest, Nuaillé, France) containing, 60 mL Dulbecco's modi ed Eagle's medium (DMEM)/F12 (Gibco, Thermo Scienti c, Waltham, MA, USA), 20 mL rat blood, 100 U/mL penicillin (Gibco), 100 µg/mL streptomycin (Gibco), and 5 U/mL heparin (Gibco) [17]. All of the donor livers were ushed with 10 mL University of Wisconsin (UW) solution through the portal vein before performing machine perfusion, and the SCS group was subjected to static cold storage with UW solution.…”

“…Therefore, topical application is the preferred method of BMMSCs administration and BMMSCs therapy also has the disadvantage of poor survival in target organs [15]. We previously used a heme oxygenase-1 (HO-1) gene transfection of BMMSCs to improve the viability of BMMSCs in target organs and to enhance and optimize the effect of BMMSCs [16,17]. In addition, normothermic machine perfusion (NMP) is a novel method of organ preservation that maintains a temperature close to the physiological state and supplies oxygen and energy substrates in vitro.…”

“…In addition, normothermic machine perfusion (NMP) is a novel method of organ preservation that maintains a temperature close to the physiological state and supplies oxygen and energy substrates in vitro. This provides improved protection of DCD liver grafts and the prognosis of DCD LT. Our previous studies found that NMP-perfused HO-1/BMMSCs heavily colonize the transplanted liver and exhibit excellent protection [17,18].…”