Protective Effects of Bone Marrow Mesenchymal Stem Cells (BMMSCS) Combined with Normothermic Machine Perfusion on Liver Grafts Donated After Circulatory Death via Reducing the Ferroptosis of Hepatocytes

BACKGROUND: To improve the quality of liver grafts from extended-criteria donors donated after circulatory death (DCD), this study explored whether bone marrow mesenchymal stem cells (BMMSCs) combined with normothermic machine perfusion (NMP) have protective effects on DCD donor livers and the effects of ferroptosis in this procedure. MATERIAL/METHODS: Twenty-four male rat DCD donor livers were randomly and averagely divided into normal, static cold storage (SCS), NMP, and NMP combined with BMMSCs groups. Liver function, bile secretion, and pathological features of DCD donor livers were detected to evaluate the protective effects of NMP and BMMSCs on DCD donor livers. Hydrogen peroxide was used to induce an oxidative stress model of hepatocyte IAR-20 cells to evaluate the protective effects of BMMSCs in vitro. RESULTS: Livers treated with NMP combined with BMMSCs showed better liver function, relieved histopathological damage, reduced oxidative stress injury and ferroptosis, and the mechanism of reduction was associated with downregulation of intracellular reactive oxygen species (ROS) and free Fe(2+) levels. BMMSCs showed significant protective effects on the ultrastructure of DCD donor livers and ROS-induced injury to IAR-20 cells under electron microscopy. BMMSCs also significantly improved the expression level of microtubule-associated protein 1 light chain 3 (LC3)-II in both DCD donor livers and ROS-induced injured IAR-20 cells, including upregulating the expression of ferritin. CONCLUSIONS: BMMSCs combined with NMP could reduce the level of ROS and free Fe(2+) in oxidative stress damaged rat DCD donor livers, potentially reduce the ferroptosis in hepatocytes, and repair both morphology and function of DCD donor livers.