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George K. Michalopoulos, MD, PhD

Professor of Pathology, Division of Experimental Pathology

Dr. George K. Michalopoulos received his medical doctoral degree at Athens University School of Medicine in 1969. A residency in Anatomic Pathology and a PhD in Oncology was obtained at the Wisconsin Medical Center in Madison in 1977. Dr. Michalopoulos moved to Duke University as Assistant Professor in 1977 and stayed at Duke University until 1991. He then moved to Pittsburgh as Professor and Chairman of the Department of Pathology in April, 1991, a role he served in through April, 2023. He also served as Associate Vice Chancellor for Health Sciences and Interim Dean of the School of Medicine from November, 1995, until November, 1998.

Awards
2012 - University of Pittsburgh Distinguished Professor
Research Interests

Our laboratory is investigating the mechanisms leading to initiation and termination of liver regeneration and their relevance to hepatic neoplasia. We have found that a key process associated with initiation is activation of extracellular matrix (ECM) remodeling by urokinase, leading to local and systemic release of activated HGF. Both HGF and EGF receptors are activated by tyrosine phosphorylation at 30 minutes after initiation of the regenerative process. HGF and the ligands of EGFR are unique in their capacity to stimulate hepatocyte DNA synthesis in primary cultures and in unoperated animals. Other regulating signaling systems include TNF, IL6, norepinephrine, bile acids, leptin, serotonin, etc. These signaling systems differ from HGF and EGFR ligands in that they do not stimulate hepatocyte DNA synthesis in vivo or in culture. Their role is essential, however, in coordinating the intracellular signals that mediate entry of hepatocytes into DNA synthesis. ECM signaling is also important in termination of liver regeneration and in adjustment of the final weight of the regenerated liver. Mice with hepatocyte-specific elimination of ILK (integrin linked kinase) have defective integrin signaling and they do not properly terminate the regenerative process. The final liver weight in the hepatocyte-specific ILK KO mice is about 60% higher than the weight at the time of hepatectomy. These mice also respond with excessive liver enlargement in response to chemical xenobiotics such as phenobarbital and TCPOBOP. Regulation of nuclear receptors and Yap protein (target of the Hippo kinase mammalian homologs MST1 and MST2) as well as alterations in hepatic integrins and extracellular matrix proteins appear to be involved. The GPI linked protein known as Glypican 3 (GPC3), produced excessively by hepatocellular carcinomas, is also involved in termination of proliferation of hepatocytes and non-parenchymal cells. We have found that GPC3, in conjunction with the tetraspanin CD81, exerts anti-proliferative signals towards the end of regeneration. Mice over-expressing GPC3 have severe defects in liver regeneration.

The signaling systems operating in liver regeneration may also be involved in hepatic neoplasia, especially hepatocellular carcinoma (HCC). In a recent study of genomics of HCC we discovered that the most frequent small deletions occur in genes controlling important signaling pathways associated with liver regeneration. The gene LSP1 was associated with the most genomic alterations (51 of 98 cases of HCC examined) and it controls the RAF-MEK-ERK pathway. PTPRD, the second most frequently gene (28/98 cases) controls activation of STAT3, an important signaling molecular for hepatocyte proliferation. MAML2 and RSU1, also majorly affected, control Notch and ILK signaling. All these are hepatocyte growth suppressor genes and their deletions accelerate growth of neoplastic hepatocytes.

Further studies from our lab using chimeric livers in rats and organoid cultures have demonstrated that in severely suppressed proliferation of biliary cells, periportal hepatocytes have the capacity to trans-differentiate to biliary epithelial cells and rescue the biliary compartment. We also verified that the process of transdifferentiation in which biliary cells and hepatocytes acquire transcription factors of each other also occurs in human liver failure and chronic biliary disease. Overall, our laboratory is exploring pathways of organ regeneration using liver as a quintessential paradigm. The studies have opened new understandings in liver regeneration and control of the "hepatostat" program regulating liver size. They have also connected signaling pathways altered in neoplasia to pathways related to liver regeneration and established the capacity of mature epithelial cells (biliary and hepatocytic) to function as stem cells for each other.

Representative Publications

NIH Research

View Dr. Michalopoulos' NIH RePORT on nih.gov

Selected Publications

View Dr. Michalopoulos' publications on PubMed

  1. Michalopoulos GK. Mechanocrine signaling, Yap, HB-EGF, and liver regeneration. Hepatology. 2025 Aug 1;82(2):286-288. doi: 10.1097/HEP.0000000000001126. Epub 2024 Oct 17. PMID: 39417846.

  2. Michalopoulos GK. Reinterpreting the True Cause and Nature of Unexpected Liver Lumps. Am J Pathol. 2025 Mar;195(3):338-340. doi: 10.1016/j.ajpath.2024.09.012. PMID: 39988412; PMCID: PMC11841487.

  3. Michalopoulos GK. Hepatocytes of mice and men: Different regenerative signals? Hepatology. 2024 Jun 1;79(6):1246-1248. doi:10.1097/HEP.0000000000000693. Epub 2023 Nov 16. PMID: 37972957.

  4. Bano S, Copeland MA, Stoops JW, Orr A, Jain S, Paranjpe S, Mooli RGR, Ramakrishnan SK, Locker J, Mars WM, Michalopoulos GK, Bhushan B. Hepatocyte-specific Epidermal Growth Factor Receptor Deletion Promotes Fibrosis but has no Effect on Steatosis in Fast-food Diet Model of Metabolic Dysfunction-associated Steatotic Liver Disease. Cell Mol Gastroenterol Hepatol. 2024;18(4):101380. doi: 10.1016/j.jcmgh.2024.101380. Epub 2024 Jul 20. PMID: 39038606; PMCID: PMC11387264.

  5. Koral K, Bhushan B, Orr A, Stoops J, Bowen WC, Copeland MA, Locker J, Mars WM, Michalopoulos GK. Lymphocyte-Specific Protein-1 Suppresses Xenobiotic-Induced Constitutive Androstane Receptor and Subsequent Yes-Associated Protein-Activated Hepatocyte Proliferation. Am J Pathol. 2022 Jun;192(6):887-903. doi: 10.1016/j.ajpath.2022.03.010. Epub 2022 Apr 4. PMID: 35390317; PMCID: PMC9194659.

  6. Bhushan B, Molina L, Koral K, Stoops JW, Mars WM, Banerjee S, Orr A, Paranjpe S, Monga SP, Locker J, Michalopoulos GK. Yes-Associated Protein Is Crucial for Constitutive Androstane Receptor-Driven Hepatocyte Proliferation But Not for Induction of Drug Metabolism Genes in Mice. Hepatology. 2021May;73(5):2005-2022. doi: 10.1002/hep.31521. PMID: 32794202; PMCID: PMC7885729.

  7. Michalopoulos GK, Bhushan B. Liver regeneration: biological and pathological mechanisms and implications. Nat Rev Gastroenterol Hepatol. 2021 Jan;18(1):40-55. doi: 10.1038/s41575-020-0342-4. Epub 2020 Aug 6. PMID: 32764740.

  8. Xue Y, Bhushan B, Mars WM, Bowen W, Tao J, Orr A, Stoops J, Yu Y, Luo J, Duncan AW, Michalopoulos GK. Phosphorylated Ezrin (Thr567) Regulates Hippo Pathway and Yes-Associated Protein (Yap) in Liver. Am J Pathol. 2020 Jul;190(7):1427-1437. doi: 10.1016/j.ajpath.2020.03.014. Epub 2020 Apr 11. PMID: 32289287; PMCID: PMC10069283.

  9. Bhushan B, Michalopoulos GK. Role of epidermal growth factor receptor in liver injury and lipid metabolism: Emerging new roles for an old receptor. Chem Biol Interact. 2020 Jun 1;324:109090. doi: 10.1016/j.cbi.2020.109090. Epub 2020 Apr 10. PMID: 32283070.

  10. Bhushan B, Banerjee S, Paranjpe S, Koral K, Mars WM, Stoops JW, Orr A, Bowen WC, Locker J, Michalopoulos GK. Pharmacologic Inhibition of Epidermal Growth Factor Receptor Suppresses Nonalcoholic Fatty Liver Disease in a Murine Fast-Food Diet Model. Hepatology. 2019 Nov;70(5):1546-1563. doi: 10.1002/hep.30696. Epub 2019 Jun 19. PMID: 31063640.

  11. Bhushan B, Stoops JW, Mars WM, Orr A, Bowen WC, Paranjpe S, Michalopoulos GK. TCPOBOP-Induced Hepatomegaly and Hepatocyte Proliferation are Attenuated by Combined Disruption of MET and EGFR Signaling. Hepatology. 2019 Apr;69(4):1702-1718. doi: 10.1002/hep.30109. Epub 2018 Dec 31. PMID: 29888801;PMCID: PMC6289897.

  12. Tsagianni A, Mars WM, Bhushan B, Bowen WC, Orr A, Stoops J, Paranjpe S, Tseng GC, Liu S, Michalopoulos GK. Combined Systemic Disruption of MET and Epidermal Growth Factor Receptor Signaling Causes Liver Failure in Normal Mice. Am J Pathol. 2018 Oct;188(10):2223-2235. doi: 10.1016/j.ajpath.2018.06.009. Epub 2018 Jul 20. PMID: 30031724; PMCID: PMC6168971.

  13. Michalopoulos GK. The Regenerative Altruism of Hepatocytes and Cholangiocytes. Cell Stem Cell. 2018 Jul 5;23(1):11-12. doi: 10.1016/j.stem.2018.06.006. PMID: 29979985.

  14. Michalopoulos GK. Hepatostat: Liver regeneration and normal liver tissue maintenance. Hepatology. 2017 Apr;65(4):1384-1392. doi: 10.1002/hep.28988. Epub 2017 Mar 6. PMID: 27997988.

  15. Paranjpe S, Bowen WC, Mars WM, Orr A, Haynes MM, DeFrances MC, Liu S, Tseng GC, Tsagianni A, Michalopoulos GK. Combined systemic elimination of MET and epidermal growth factor receptor signaling completely abolishes liver regeneration and leads to liver decompensation. Hepatology. 2016 Nov;64(5):1711-1724. doi: 10.1002/hep.28721. Epub 2016 Oct 1. PMID: 27397846; PMCID: PMC5074871.