AntagomiR-199a Enhances the Liver Protective Effect of Hypoxia-Preconditioned BM-MSCs in a Rat Model of Reduced-Size Liver Transplantation.

Abstract

Reduced-size liver transplantation (LT) was invented to overcome the shortage of donor livers; however, it has proven to be more susceptible to ischemia-reperfusion injury. Bone marrow-derived mesenchymal stem cell infusion has been shown to be protective following LT. Optimization of MSC infusion has been performed, among which hypoxia preconditioning and miRNA modulation have shown promise. MiR-199a inhibition was reported to induce angioneogenesis; however, whether mir-199a inhibition enhances the protective effect of Bone marrow-derived mesenchymal stem cells in LT remains unknown. In this study, we combined antagomiR-199a with hypoxia-preconditioned MSC (H-MSC) infusion to discuss their effect and mechanism in a rat model of reduced-size LT. A reduced-size LT model was constructed and H-MSCs were intraportally injected during operation. AgomiR-199a and antagomir-199a were injected through the caudal vein once a day after LT. The level of apoptosis and proinflammatory cytokines were measured. An anti-vascular endothelial growth factor (VEGF) antibody was injected to further explore the underlying mechanism. AntagomiR-199a plus H-MSC not only significantly decreased ALT and AST 72 h after LT but also ameliorated the level of apoptosis and inhibited inflammatory reactions. On the contrary, agomir-199a reduced the protective effect of the H-MSC infusion. In terms of mechanism, the liver protective effect of miR-199a inhibition was abolished by treatment with a VEGF-neutralizing antibody. AntagomiR-199a enhanced the protective effect of H-MSCs infusion via activation of the hypoxia induction factor 1α/VEGF axis.