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 and he continues to serve in that role. He also served as Associate Vice Chancellor for Health Sciences and Interim Dean of the School of Medicine from November, 1995, until November, 1998.
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.
View Dr. Michalopoulos' NIH RePORT on nih.gov
View Dr. Michalopoulos' publications on PubMed
- Fontes P, Lopez R, van der Plaats A, Vodovotz Y, Minervini M, Scott V, Soltys K, Shiva S, Paranjpe S, Sadowsky D, Barclay D, Zamora R, Stolz D, Demetris A, Michalopoulos G, Marsh JW. Liver Preservation With Machine Perfusion and a Newly Developed Cell-Free Oxygen Carrier Solution Under Subnormothermic Conditions. Am J Transplant. 2015 Jan 22. doi: 10.1111/ajt.12991. [Epub ahead of print] PubMed, PMID: 25612645.
- Chen ZH, Yu YP, Michalopoulos G, Nelson J, Luo JH. The DNA replication licensing factor miniature chromosome maintenance 7 is essential for RNA splicing of epidermal growth factor receptor, c-met and platelet derived growth factor receptor. J Biol Chem. 2014 Nov 25. pii: jbc.M114.622761. [Epub ahead of print] PubMed PMID: 25425645.
- Yu YP, Ding Y, Chen Z, Liu S, Michalopoulos A, Chen R, Gulzar ZG, Yang B, Cieply KM, Luvison A, Ren BG, Brooks JD, Jarrard D, Nelson JB, Michalopoulos GK, Tseng GC, Luo JH. Novel fusion transcripts associate with progressive prostate cancer. Am J Pathol. 2014 Oct;184(10):2840-9. doi: 10.1016/j.ajpath.2014.06.025.. PubMed PMID: 25238935; PubMed Central PMCID: PMC4188871.
- Koral K, Paranjpe S, Bowen WC, Mars W, Luo J, Michalopoulos GK. Leukocyte-specific protein 1: a novel regulator of hepatocellular proliferation and migration deleted in human hepatocellular carcinoma. Hepatology. 2015 Feb;61(2):537-47. doi: 10.1002/hep.27444. Epub 2014 Dec 24. PubMed PMID: 25234543; PubMed Central PMCID: PMC4303494.
- Michalopoulos GK. Advances in liver regeneration. Expert Rev Gastroenterol Hepatol. 2014 Jun 26:1-11. [Epub ahead of print] PubMed PMID: 24964729.
- Norris CA, He M, Kang LI, Ding MQ, Radder JE, Haynes MM, Yang Y, Paranjpe S, Bowen WC, Orr A, Michalopoulos GK, Stolz DB, Mars WM. Synthesis of IL-6 by hepatocytes is a normal response to common hepatic stimuli. PLoS One. 2014 Apr 24;9(4):e96053. doi: 10.1371/journal.pone.0096053. eCollection 2014. PubMed PMID: 24763697. PubMed Central PMCID: PMC3999098.
- Bowen WC, Michalopoulos AW, Orr A, Ding MQ, Stolz DB, Michalopoulos GK. Development of a chemically defined medium and discovery of new mitogenic growth factors for mouse hepatocytes: mitogenic effects of FGF1/2 and PDGF. PLoS One. 2014 Apr 17;9(4):e95487. doi: 10.1371/journal.pone.0095487. eCollection 2014. PubMed PMID: PMID: 24743506. PubMed Central PMCID: PMC3990636.
- Michalopoulos GK. NRF2, not always friendly but perhaps misunderstood. Hepatology. 2014 Feb 23. doi: 10.1002/hep.27090. [Epub ahead of print] PubMed PMID: 24700292.
- Michalopoulos GK. The liver is a peculiar organ when it comes to stem cells. Am J Pathol. 2014 May;184(5):1263-7. doi: 10.1016/j.ajpath.2014.02.020. Epub 2014 Mar 27. PubMed PMID: 24681248. PubMed Central PMCID: PMC4005979.
- Davison JM, Yee M, Krill-Burger JM, Lyons-Weiler MA, Kelly LA, Sciulli CM, Nason KS, Luketich JD, Michalopoulos GK, LaFramboise WA. The degree of segmental aneuploidy measured by total copy number abnormalities predicts survival and recurrence in superficial gastroesophageal adenocarcinoma. PLoS One. 2014 Jan 16;9(1):e79079. doi: 10.1371/journal.pone.0079079. eCollection 2014. PubMed PMID: 24454681. PubMed Central PMCID: PMC3894223.
- Michalopoulos, GK. Principles of Liver Regeneration and Growth Homeostasis. Compr. Physiol. 2013 Jan 1;3 (1):485-513. PMID: 23720294.
- Bhave VS, Mars W., Donthamsetty S., Zhang X., Tan L., Luo J., Bowen WC, Michalopoulos GK. Regulation of Liver Growth by Glypican 3, CD81, Hedgehog and hhex. Am. J. Pathol. 2013 Jul;183 (1):159-9. PMID: 23665349.
- Nejak-Bowen, KN, Orr AV, Bowen WC Jr., Michalopoulos GK. Gliotoxin-induced Changes in Rat Liver Regeneration after Partial Hepatectomy. Liver Int. 2013 Aug;33 (7):1044-55. PMID: 23552057.