George Michalopoulos , Professor
Chairman of Pathology
MD, Athens University Medical School, 1970
PhD, University of Wisconsin, 1977
Email: michalopoulosgk@upmc.edu
Dr. Michalopoulos's laboratory uses the differentiated cells of the liver (hepatocytes) as models to understand the mechanisms that regulate growth of complex differentiated cells and whole organs. His laboratory identified and isolated the substance now known as Hepatocyte Growth Factor/Scatter Factor (HGF), and also identified the receptor for HGF encoded by the proto-oncogene c-met.
The liver regenerates to full size after up to 2/3 of its mass is removed. Michalopoulos's lab has shown that levels of activated HGF rise within 60 minutes in the plasma during liver regeneration and is part of the mitogenic signal leading hepatocytes to proliferation. An enzyme called urokinase has been shown to activate both HGF and plasminogen and induces a cascade of activated matrix degrading enzymes known as metalloproteinases. Inhibition of the HGF receptor by silencing RNA inhibits most of the early events associated with liver regeneration. Matrix signaling through integrins is associated with termination signals for liver regeneration.
Hepatocytes grown in culture lose their differentiation and proliferate as independent clones. When complex matrix gels (Matrigel) are applied to the cultures, hepatocyte differentiation is rapidly restored. Mixed cultures of hepatocytes and non-parenchymal cells develop into three-dimensional cultures with specific histology.
Recent Publication
Gkretsi V, Bowen WC, Yang Y, Wu C, Michalopoulos GK. Integrin-linked kinase is involved in matrix-induced hepatocyte differentiation. Biochem Biophys Res Commun. 2007 Feb 16;353(3):638-43. Epub 2006 Dec 20. PMID: 17194454
Luo JH, Ren B, Keryanov S, Tseng GC, Rao UN, Monga SP, Strom S, Demetris AJ, Nalesnik M, Yu YP, Ranganathan S, Michalopoulos GK. Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas. Hepatology. 2006 Oct;44(4):1012-24. PMID: 17006932
Khan Z, Michalopoulos GK, Stolz DB. Peroxisomal localization of hypoxia-inducible factors and hypoxia-inducible factor regulatory hydroxylases in primary rat hepatocytes exposed to hypoxia-reoxygenation. Am J Pathol. 2006 Oct;169(4):1251-69. PMID: 17003483
Kohler C, Bell AW, Bowen WC, Monga SP, Fleig W, Michalopoulos GK. Expression of Notch-1 and its ligand Jagged-1 in rat liver during liver regeneration. Hepatology. 2004 Apr;39(4):1056-65. PMID: 15057910
