Gyongyi Szabo,
Professor & Vice Chair for Research, Department of Medicine,
University of Massachusetts Medical School
Gyongyi Szabo, MD, PhD, FAASDL, FACP, AGAF is the Worcester Foundation for Biomedical Sciences Endowed Chair, Associate Vice Provost for Interprofessional Education, Professor and Vice Chair of Medicine at the University of Massachusetts Medical School. Dr. Szabo is an internationally recognized leader in the field of liver immunology and inflammation. Her translational research and clinical investigations focus on alcoholic hepatitis, non-alcoholic fatty liver disease and viral hepatitis. She is the lead investigator on an NIH-supported multicenter clinical trial on alcoholic hepatitis. Her laboratory studies molecular mechanisms of inflammation and innate immunity to identify therapeutic targets and to explore translation of bench to bedside opportunities in liver diseases. Her recent research focuses on the role of Toll-like receptor and Nod-like receptor signaling pathways in alcoholic and non-alcoholic fatty liver diseases and the importance of micro-RNAs as biomarkers. In recognition of her contributions to medical research she was recently elected to the Hungarian Academy of Sciences. She serves on the Editorial Board of Hepatology, Nature Reviews Gartoenterology & Hepatology and on the Advisory Board of several agencies including the NIH ExRNA Consortium. She is President of the American Association for the Study of Liver Diseases in 2015.
Extracellular Vesicles and Their microRNA Cargo Serve as Biomarkers and Communicators in Liquid Biopsies
Liquid biopsies such as serum or plasma are of great interest in the diagnosis and prognostication of liver diseases with the aim to replace the current “gold standard” of invasive liver biopsy. Liquid biopsy samples are enriched in Extracellular vesicles (EVs) that contain nucleic acids including microRAs as well as proteins. EVs produced in the liver by most cell types including hepatocytes and Kupffer cells, the liver resident macrophages are found in the circulation. We have previously reported that different types of liver injury (alcoholic, drug-induced or inflammation-related) result in increased levels of circulating EVs and these EVs are enriched in miR-122 indicating hepatocyte injury or miR-155 indicating liver inflammation. miR-122 is abundant in hepatocytes and circulating miR-122 was found in liver injury. We hypothesized that microRNA cargo of Extracellular Vesicle (EV) can serve as both biomarkers and organelles of communication between hepatocytes and immune cells in alcoholic hepatitis. EVs isolated from sera of chronic alcohol-fed (5 weeks Lieber DeCarli diet) or pair-fed mice and patients with alcoholic hepatitis, were characterized by western blot, nanoparticle tracking analysis system and miRNA analysis. The number of circulating EVs was significantly increased in alcohol-fed mice compared to controls. Exosomes represented most of the EVs (~80%). MicroRNA array of EVs revealed a significant increase of 7 inflammatory miRs (miR-192, 122, 30a, 744, 1246, 30b and miR-130a) in alcohol-fed mice compared to controls and of those miR-192, 122, and 30a showed excellent diagnostic value by ROC analyses. In patients with acute alcoholic hepatitis, we found a significant increase in the number of circulating EVs compared to controls with an increase in miR-192 and miR-30a in their cargo. Serum miR-122 was increased after alcohol binge drinking. In vitro, exosomes derived from ethanol-treated human hepatocytes were taken up by monocytes and transferred mature miR-122 into monocytes. This horizontally transferred miR-122 inhibited hemeoxygenase-1 expression, a target of miR-122 and sensitized monocytes to LPS stimulation to increase production of pro-inflammatory cytokines, TNF-a and IL-1ß; these effects were inhibited by exosome-mediated delivery of a miR-122 inhibitor in monocytes. Our results indicate that levels of EVs and their micoRNA signature can serve as biomarkers of alcoholic hepatitis. We discovered a novel EV-mediated mechanism of alcohol-induced communication between hepatocytes and monocytes by transferring hepatocyte-derived miR-122 that reprograms monocytes promoting inflammation in alcoholic hepatitis. These studies suggest that investigations of liquid biopsies have a great potential both in biomarker discovery and better understanding of disease mechanisms.
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