Identification of hepatocytic and bile ductular cell lineages and candidate stem cells in bipolar ductular reactions in cirrhotic human liver

Zhou, Haoran; Rogler, Leslie E.; Teperman, Lewis; Morgan, G. W.; Rogler, Charles E.

doi:10.1002/hep.21557

Cited by 131 publications

(123 citation statements)

References 24 publications

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“…The biliary lineage of these cells was indicated by the fact that they expressed CFTR (a very specific marker of cholangiocytes in the liver) in CF ( Figure 2B) as well as in PBC and PSC (not shown). A contribution of hepatocytic or stem cell lineages to the ductular reaction was previously reported mainly in severe and end-stage liver disease, 37,38 and was less likely in these patients who, in majority, had early-stage disease. Ki-67 positivity in ductular cells was detected essentially in patients with CF liver disease, suggesting that cholangiocytes proliferate more actively in this disease than in PBC or PSC.…”

Section: Discussionmentioning

confidence: 71%

Ezrin-Radixin-Moesin-Binding Phosphoprotein (EBP50), an Estrogen-Inducible Scaffold Protein, Contributes to Biliary Epithelial Cell Proliferation

Fouassier

Rosenberg

Mergey

et al. 2009

The American Journal of Pathology

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Ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) anchors and regulates apical membrane proteins in epithelia. EBP50 is inducible by estrogen and may affect cell proliferation, although this latter function remains unclear. The goal of this study was to determine whether EBP50 was implicated in the ductular reaction that occurs in liver disease. EBP50 expression was examined in normal human liver, in human cholangiopathies (ie, cystic fibrosis, primary biliary cirrhosis, and primary sclerosing cholangitis), and in rats subjected to bile-duct ligation. The regulation of EBP50 by estrogens and its impact on proliferation were assessed in both bile duct-ligated rats and Mz-Cha-1 human biliary epithelial cells. Analyses of cell isolates and immunohistochemical studies showed that in normal human liver, EBP50 is expressed in the canalicular membranes of hepatocytes and, together with ezrin and cystic fibrosis transmembrane conductance regulator, in the apical domains of cholangiocytes. In both human cholangiopathies and bile duct-ligated rats, EBP50 was redistributed to the cytoplasmic and nuclear compartments. EBP50 underwent a transient increase in rat cholangiocytes after bile-duct ligation, whereas such expression was down-regulated in ovariectomized rats. In addition, in Mz-Cha-1 cells, EBP50 underwent upregulation and intracellular redistribution in response to 17␤-estradiol, whereas its proliferation was inhibited by siRNA-mediated EBP50 knockdown. These results indicate that both the expression and distribution of EBP50 are regulated by estrogens and contribute to the proliferative response in biliary epithelial cells. (Am J

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Section: Discussionmentioning

confidence: 71%

Ezrin-Radixin-Moesin-Binding Phosphoprotein (EBP50), an Estrogen-Inducible Scaffold Protein, Contributes to Biliary Epithelial Cell Proliferation

Fouassier

Rosenberg

Mergey

et al. 2009

The American Journal of Pathology

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“…In addition, the portal inflammation is closely associated with ductular reaction in periportal areas. As hepatic stem cells are speculated to reside alongside biliary epithelial cells in canal of Hering [44,45], the existence of multiple IFNinducing pathways, including TLR3 and RIG-I/MDA5, may suggest the importance of this innate immune effector pathway in the protection of putative hepatic stem cells from viral infection.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of Toll-like receptor 3 in intrahepatic biliary epithelial cells at sites of ductular reaction in diseased livers

et al. 2008

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“…Structures containing hepatocytes, BEC and intermediate cell types were recently described in a 'bipolar' ductular reaction. [4][5][6]32 The above studies have well documented the appearance of alternate single-gene markers in hepatic cells in different disease states. Expression of genes specific to cell types (markers) has always been used as basis for assessing differentiation status of a given cell.…”

mentioning

confidence: 99%

Expression of specific hepatocyte and cholangiocyte transcription factors in human liver disease and embryonic development

Limaye

Alarcón

Walls

et al. 2008

Laboratory Investigation

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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.

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Identification of hepatocytic and bile ductular cell lineages and candidate stem cells in bipolar ductular reactions in cirrhotic human liver

Cited by 131 publications

References 24 publications

Ezrin-Radixin-Moesin-Binding Phosphoprotein (EBP50), an Estrogen-Inducible Scaffold Protein, Contributes to Biliary Epithelial Cell Proliferation

Ezrin-Radixin-Moesin-Binding Phosphoprotein (EBP50), an Estrogen-Inducible Scaffold Protein, Contributes to Biliary Epithelial Cell Proliferation

Increased expression of Toll-like receptor 3 in intrahepatic biliary epithelial cells at sites of ductular reaction in diseased livers

Expression of specific hepatocyte and cholangiocyte transcription factors in human liver disease and embryonic development

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