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Παρασκευή 9 Φεβρουαρίου 2018

Extracellular vesicles from human liver stem cells reduce injury in an ex vivo normothermic hypoxic rat liver perfusion model

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ABSTRACTBackgroundThe gold standard for organ preservation before transplantation is static cold storage, which is unable to fully protect suboptimal livers from ischemia/reperfusion injury. An emerging alternative is normothermic machine perfusion (NMP), which permits organ reconditioning. Here, we aimed to explore the feasibility of a pharmacological intervention on isolated rat livers by using a combination of NMP and human liver stem cells-derived extracellular vesicles (HLSC-EV).MethodsWe established an ex vivo murine model of NMP capable to maintain liver function despite an ongoing hypoxic injury induced by hemodilution. Livers were perfused during 4 hours without (control group, n=10) or with HLSC-EV (treated group, n=9). Bile production was quantified; perfusate samples were collected hourly to measure metabolic (pH, pO2, pCO2) and cytolysis parameters (AST, ALT, LDH). At the end of perfusion, we assessed HLSC-EV engraftment by immunofluorescence, tissue injury by histology, apoptosis by TUNEL assay, and tissue HIF-1α and TGF-β1 RNA expression by quantitative RT-PCR.ResultsDuring hypoxic NMP, livers were able to maintain homeostasis and produce bile. In the treated group, AST (p=0.018) and LDH (p=0.032) levels were significantly lower than those of the control group at 3 hours of perfusion, and AST levels persisted lower at 4 hours (p=0.003). By the end of NMP, HLSC-EV had been uptaken by hepatocytes and EV treatment significantly reduced histological damage (p=0.030), apoptosis (p=0.049), and RNA over-expression of HIF-1α (p

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