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Expression of Specific Hepatocyte and Cholangiocyte Transcription Factors

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Expression of Specific Hepatocyte and Cholangiocyte Transcription Factors Laboratory Investigation (2008) 88, 865–872 & 2008 USCAP, Inc All rights reserved 0023-6837/08 $30.00 Expression of specific hepatocyte and cholangiocyte transcription factors in human liver disease and embryonic development Pallavi B Limaye, Gabriela Alarco´n, Andrew L Walls, Michael A Nalesnik, George K Michalopoulos, Anthony J Demetris and Erin R Ochoa Transcription factors are major determinants of cell-specific gene expression in all cell types. Studies in rodent liver have shown that alterations in transcription factor expression determine lineage specification during fetal liver development and signify transdifferentiation of cells of the biliary compartment into ‘oval’ cells and eventually hepatocytes in adult liver. We examined the cellular localization of hepatocyte- or BEC-associated transcription factors in human fetal and adult liver and in diseases in which transdifferentiation between hepatocytes and biliary cells may play a role. In the normal adult human liver, hepatocyte nuclear factor (HNF)4a and HNF6 appeared exclusively in hepatocytes; HNF1b, HNF3a, and HNF3b were observed only in BEC. During fetal development both BEC and hepatocytes expressed HNF3a, HNF3b, and HNF6. HNF1a was expressed only in fetal hepatocytes. We further examined expression of transcription factors in massive hepatic necrosis and in specific types of chronic liver disease. Hepatocyte-associated transcription factors HNF4a and HNF6 also appeared in BEC in massive hepatic necrosis and chronic hepatitis C virus infection. Similarly, HNF3b that is expressed only in BEC in normal adult liver was also observed in hepatocytes in primary biliary cirrhosis and chronic biliary obstruction. These data mimic previous findings in rodents in which hepatocyte-associated transcription factors appear in biliary cells prior to emergence of oval cells, which function as progenitor cells for hepatocytes when the regenerative capacity of the latter is compromised. Laboratory Investigation (2008) 88, 865–872; doi:10.1038/labinvest.2008.56; published online 23 June 2008 KEYWORDS: transcription factors; embryonic human liver; transdifferentiation; hepatocytes; biliary epithelial cells Hepatocytes and biliary epithelial cells (BEC) are distinctly specific cell types, cells with promiscuous expression of both different cell types in the adult liver. In addition to trans- hepatocytic and BEC single-gene markers are often seen in cription factors expressed commonly in many cell types, chronic liver disease.3–7 The appearance of ‘marker genes’ there are transcription factors expressed (in the adult liver) from the other (hepatocyte or BEC) cell type suggests that a only in hepatocytes or BEC. Expression of transcription reprogramming in gene expression is taking place, as an factors is crucial in determining specificity of cell differ- adaptation to a specific pathobiologic or physiological chal- entiation. Cellular specificity in gene expression is in large lenge. Although the appearance of single-gene markers of part controlled by nuclear protein complexes, which include alternate specificity is well documented, changes in trans- transcription factors. The latter impart specificity to gene cription factors controlling in human liver have not been expression based on cell type. Thus, emergence of new characterized. transcription factors in fully differentiated cells transcends The regenerative capacities of hepatocytes and BEC have the appearance of mere single-gene markers and is inter- been tested in many experimental studies in rodents. In preted to signify large-scale reprogramming in gene expres- uncomplicated liver regeneration after partial hepatectomy or sion.1,2 Whereas in normal adult liver, the expression of during BEC proliferation following bile duct ligation, hepato- hepatocyte- or BEC-associated single genes is localized to the cytes or BEC respectively proliferate to generate more cells Department of Pathology, Division of Transplantation Pathology, Montefiore University Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA Correspondence: Dr ER Ochoa, MD, Department of Pathology, Division of Transplantation Pathology, UPMC Montefiore, University of Pittsburgh School of Medicine, Suite E-739, 200 Lothrop Street, Pittsburgh, PA 15213-2582, USA. E-mail: [email protected] Received 29 January 2008; accepted 02 April 2008 www.laboratoryinvestigation.org | Laboratory Investigation | Volume 88 August 2008 865 Transcription factors in human liver disease PB Limaye et al of their type.8–10 If, however, the capacity of hepatocytes or mediate differentiation between hepatocytes and BEC. BEC to regenerate more of their own is impaired, then (in Structures containing hepatocytes, BEC and intermediate rodent systems) hepatocytes and BEC can transdifferentiate cell types were recently described in a ‘bipolar’ ductular into each other. BEC (from canals of Hering and/or portal reaction.4–6,32 The above studies have well documented the ductules) proliferate transiently to generate ‘oval’ cells which appearance of alternate single-gene markers in hepatic cells in undergo gradual morphologic and biochemical changes to different disease states. Expression of genes specific to cell become hepatocytes.11–15 Oval cells express both biliary- and types (markers) has always been used as basis for assessing hepatocyte-associated genes. There are two pieces of evidence differentiation status of a given cell. However, gene expres- supporting the biliary origin of the oval cells. In the first piece sion patterns (including cell-specific markers) in any cell type of evidence, oval cells do not appear when BEC are subjected are determined in large part by the expression of specific to lethal toxic injury prior to the induction of the oval cell transcription factors, which, in synergy with epigenetic protocol.16 The second piece of evidence is the appearance of changes, determine cell differentiation and define cell lineage. hepatocyte-associated transcription factors in BECs very Thus we investigated expression of hepatocyte- or BEC- soon after the initiation of the oval cell protocol.17 We have associated transcription factors in both hepatocytes and BEC also shown in rats that when the capacity of BEC to pro- in human liver, as a tool to determine initiation of liferate is impaired by delivering a toxic injury by DAPM, promiscuous altered gene expression patterns between more BEC can be formed by transdifferentiation of periportal hepatocytes and biliary cells during chronic liver disease, hepatocytes.18 comparable to the changes seen in impaired regeneration Hepatocytic and BEC lineage is specified in part by a set of models in rodents. specific liver-enriched transcription factors.1,2,19,20 Studies with knockout mice have shown that hepatocyte nuclear MATERIALS AND METHODS factor (HNF)1a and HNF4a regulate transcription of genes Case Selection essential for the hepatocytic cell lineage,21–23 whereas HNF1b With approval from the IRB of the University of Pittsburgh and HNF6 are involved in development of the gallbladder (IRB no. 0501051), paraffin-embedded liver sections were and bile ducts.24–26 Previous studies with rodents have shown obtained from the archives of the Department of Pathology, that the earliest step in the generation of the oval cells is the University of Pittsburgh Medical Center. Specimens appearance of hepatocyte-associated transcription factors in were obtained from five cases each of first, second, and BEC of portal ductules and canals of Hering.17,27 This is third trimester fetal liver tissue, and normal adult (NL). direct evidence of initiation of large-scale gene reprogram- Data presented in this article were collected from four ming, as transcription factors affect expression of multiple cases of end-stage cirrhosis from chronic HCV infection, genes associated with differentiation of specific cell types. In five cases of massive hepatic necrosis (causes included HBV this model, appearance of hepatocyte-associated transcrip- infection, autoimmune hepatitis, acetaminophen), five cases tion factors in biliary cells suggests initiation of expression of of chronic biliary obstruction (none of the cases included genes associated with hepatocyte differentiation in biliary cell pancreatic cancer), and three cases of late-stage PBC. types. This is perfectly consistent with the large-scale ex- The specimens related to specific liver diseases all represent pression of hepatocyte-associated genes in oval cells, as they end-stage liver disease in their type. They were obtained gradually transform to small and eventually regular hepato- from livers explanted for the purpose of orthotopic cytes in the AAF-hepatectomy protocol.11–13 liver transplantation. The normal adult liver tissue samples As most of the literature of expression of transcription were selected from liver specimens resected for metastatic factors in hepatic cell types derives from studies in rodents, colorectal carcinoma. we first assessed transcription factor expression in hepato- cytes versus BEC in human fetal and normal adult liver, to Immunohistochemistry provide a comparison standard with literature derived from Immunohistochemical localization studies of HNF1a, rodent-based experimental studies. We also examined the HNF1b, HNF3a, HNF3b, HNF4a, HNF6 were conducted on presence of specific transcription factors in liver diseases in formalin-fixed paraffin-embedded liver sections (4-mm which hepatocytes or biliary cells are selectively affected. thick). Corresponding
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