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George C T Yeoh - One of the best experts on this subject based on the ideXlab platform.
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attenuated liver progenitor Oval Cell and fibrogenic responses to the choline deficient ethionine supplemented diet in the balb c inbred strain of mice
Journal of Hepatology, 2007Co-Authors: Belinda Knight, Vance B Matthews, John K Olynyk, Lawrence J Abraham, Barbara Akhurst, Richard G Ruddell, Grant A Ramm, George C T YeohAbstract:Background/Aims Liver regeneration following chronic injury is associated with inflammation, the proliferation of liver progenitor (Oval) Cells and fibrosis. Previous studies identified interferon-gamma as a key mediator of Oval Cell proliferation. Interferon-γ is known to regulate Th1 Cell activities during immune challenge. Therefore, we hypothesised that progenitor Cell-mediated regeneration is associated with a Th1 immune response. Methods C57Bl/6 (normal Th1 response) and BALB/c mice (deficient in Th1 signalling) were placed on a carcinogenic diet to induce liver injury, progenitor Cell proliferation and fibrosis. Results Serum transaminases and mortality were elevated in BALB/c mice fed the diet. Proliferation of liver progenitor Cells was significantly attenuated in BALB/c animals. The pattern of cytokine expression and inflammation differed between strains. Liver fibrosis and hepatic stellate Cell activation were significantly inhibited in BALB/c mice compared to C57Bl/6. In addition, interferon-γ knockout mice also showed reduced fibrosis compared to wild type. These findings are in contrast to published results, in which interferon-gamma is shown to be anti-fibrogenic. Conclusions Our data demonstrate that the hepatic progenitor Cell response to a CDE diet is inhibited in mice lacking Th1 immune signalling and further show that this inhibition is associated with reduced liver fibrosis.
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transforming growth factor beta differentially regulates Oval Cell and hepatocyte proliferation
Hepatology, 2007Co-Authors: Lananh N Nguyen, Belinda Knight, George C T Yeoh, Nelson Fausto, Jean S Campbell, Momoko H Furuya, Lawrence A Wolfraim, Anthony P Nguyen, Matthew S Holdren, Tony W ParksAbstract:Oval Cells are hepatocytic precursors that proliferate in late-stage cirrhosis and that give rise to a subset of human hepatoCellular carcinomas. Although liver regeneration typically occurs through replication of existing hepatocytes, Oval Cells proliferate only when hepatocyte proliferation is inhibited. Transforming growth factor-β (TGF-β) is a key inhibitory cytokine for hepatocytes, both in vitro and in vivo. Because TGF-β levels are elevated in chronic liver injury when Oval Cells arise, we hypothesized that Oval Cells may be less responsive to the growth inhibitory effects of this cytokine. To examine TGF-β signaling in vivo in Oval Cells, we analyzed livers of rats fed a choline-deficient, ethionine-supplemented (CDE) diet for phospho-Smad2. Phospho-Smad2 was detected in more than 80% of hepatocytes, but staining was substantially reduced in Oval Cells. Ki67 staining, in contrast, was significantly more common in Oval Cells than hepatocytes. To understand the inverse relationship between TGF-β signaling and proliferation in Oval Cells and hepatocytes, we examined TGF-β signaling in vitro. TGF-β caused marked growth inhibition in primary hepatocytes and the AML12 hepatocyte Cell line. Two Oval Cell lines, LE/2 and LE/6, were less responsive. The greater sensitivity of the hepatocytes to TGF-β–induced growth inhibition may result from the absence of Smad6 in these Cells. Conclusion: Our results indicate that Oval Cells, both in vivo and in vitro, are less sensitive to TGF-β–induced growth inhibition than hepatocytes. These findings further suggest an underlying mechanism for the proliferation of Oval Cells in an environment inhibitory to hepatocytic proliferation. (HEPATOLOGY 2007;45:31–41.)
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liver inflammation and cytokine production but not acute phase protein synthesis accompany the adult liver progenitor Oval Cell response to chronic liver injury
Immunology and Cell Biology, 2005Co-Authors: Belinda Knight, Vance B Matthews, John K Olynyk, Lawrence J Abraham, Barbara Akhurst, Emma J Croager, Elizabeth Klinken, George C T YeohAbstract:Oval Cells are facultative liver progenitor Cells, which are invoked during chronic liver injury in order to replenish damaged hepatocytes and bile duct Cells. Previous studies have observed inflammation and cytokine production in the liver during chronic injury. Further, it has been proposed that inflammatory growth factors may mediate the proliferation of Oval Cells during disease progression. We have undertaken a detailed examination of inflammation and cytokine production during a time course of liver injury and repair, invoked by feeding mice a choline-deficient, ethionine-supplemented (CDE) diet. We show that immediately following initial liver injury, B220-expressing leucocytes transiently infiltrate the liver. This inflammatory response occurred immediately before Oval Cell numbers began to expand in the liver, suggesting that the two events may be linked. Two waves of liver cytokine production were observed during the CDE time course. The first occurred shortly following commencement of the diet, suggesting that it may represent a hepatic acute phase response. However, examination of acute phase marker expression in CDE-fed mice did not support this hypothesis. The second wave of cytokine expression correlated with the expansion of Oval Cell numbers in the liver, suggesting that these factors may mediate Oval Cell proliferation. No inflammatory signalling was detected following withdrawal of the injury stimulus. In summary, our results document a close correlation between inflammation, cytokine production and the expansion of Oval Cells in the liver during experimental chronic injury.
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hepatic expression of the tumor necrosis factor family member lymphotoxin beta is regulated by interleukin il 6 and il 1beta transcriptional control mechanisms in Oval Cells and hepatoma Cell lines
Liver International, 2005Co-Authors: Lily S Subrata, John K Olynyk, George C T Yeoh, Kim N Lowes, Elizabeth Quail, Lawrence J AbrahamAbstract:Background: Lymphotoxin-β (LT-β) plays an important role in inflammation and its promoter contains a functional nuclear factor-κB (NF-κB) element, rendering it a likely target of pro-inflammatory cytokines. Inflammatory cytokines play a central role in liver regeneration resulting from acute or chronic liver injury, with interleukin (IL)-6 signaling essential for liver regeneration induced by partial hepatectomy. In hepatic Oval Cells observed following chronic liver injury, LT-β levels are upregulated, suggesting a link between LT-β and liver regeneration. Results: The expression of LT-β in hepatic Oval Cell and hepatoCellular carcinoma Cell lines was further investigated, along with its responsiveness to IL-6 and IL-1β. Key regulatory cis-acting elements of the LT-β promoter that mediate IL-6 responsiveness (Sp/BKLF, Ets, NF-κB and Egr-1/Sp1) and IL-1β responsiveness (NF-κB and Ets) of hepatic LT-β expression were identified. The novel binding of basic Kruppel-like factor (BKLF) proteins to an apparent composite Sp/BKLF site of the LT-β promoter was shown to mediate IL-6 responsiveness. Binding of NF-κB p65/p50 heterodimers and Ets-related transcription factors to their respective sites mediates responsiveness to IL-1β. Conclusion: The identification of IL-6 and IL-1β as activators of LT-β supports their involvement in LT-β signaling in liver regeneration associated with chronic liver damage.
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oncostatin m induces an acute phase response but does not modulate the growth or maturation status of liver progenitor Oval Cells in culture
Experimental Cell Research, 2005Co-Authors: Vance B Matthews, Belinda Knight, Janina E E Tirnitzparker, James Boon, John K Olynyk, George C T YeohAbstract:Following acute injury, the liver regenerates through hepatocyte division. If this pathway is impaired, liver repair depends on the recruitment of adult liver progenitor (Oval) Cells. Mice fed a choline deficient, ethionine supplemented (CDE) diet possess substantial numbers of Oval Cells, which can be isolated, or examined in vivo. Oncostatin M (OSM) has been shown to induce maturation of murine fetal hepatoblasts into hepatocytes. We recently confirmed this in human fetal liver cultures. Here, we show that liver OSM expression increases in mice fed a CDE diet and CDE-derived Oval Cell isolates express OSM and its receptor (OSMR). Oval Cell lines (PIL Cells), as well as primary Oval Cell cultures, displayed STAT-3 phosphorylation following OSM stimulation. OSM had no effect on the growth of primary Oval Cells, but it was pro-apoptotic to PIL Cells, suggesting that the two Cell models are not directly comparable. Expression of PCNA and cyclin D1 was not affected by OSM treatment. No evidence was obtained to suggest an effect on Oval Cell maturation with OSM treatment. However, decreased albumin production, accompanied by increased expression of haptoglobin and fibrinogen, suggests that OSM induced an acute phase reaction in cultured Oval Cells.
Bryon E Petersen - One of the best experts on this subject based on the ideXlab platform.
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the role of the wnt family of secreted proteins in rat Oval stem Cell based liver regeneration wnt1 drives differentiation
American Journal of Pathology, 2010Co-Authors: Jennifer M Williams, Marda Jorgensen, Nicole Steiger, Houda Darwiche, Thomas Shupe, Bryon E PetersenAbstract:To date the molecular signals regulating activation, proliferation, and differentiation of hepatic Oval Cells are not fully understood. The Wnt family is essential in hepatic embryogenesis and implicated in hepatic carcinogenesis. This study elucidates novel findings implicating Wnt1 in directing Oval Cell differentiation during the rat 2-acetylaminofluorene (2AAF) and ⅔ partial hepatectomy (PHx) liver regeneration model. Proteins of Wnt family members were predominantly localized in pericentral hepatocytes during liver injury, Oval Cell activation, and hepatocyte regeneration. In addition, Wnt message increased coinciding with the rise in Oval Cell number, whereas protein levels peaked immediately after the height of Oval Cell proliferation. Immunohistochemical analysis demonstrated nuclear translocation of β-catenin within Oval Cells throughout the 2AAF/PHx protocol. Furthermore, RNA interference was used in vivo to confirm the physiological requirement of Wnt1 during the Oval Cell induction. Ultimately, inhibition of Wnt1 resulted in failure of Oval Cells to differentiate into hepatocytes and alternatively induced atypical ductular hyperplasia. Taken together, these data indicate that in vivo exposure to Wnt1 shRNA inhibited rat Oval Cell liver regeneration. In the absence of Wnt1 signaling, Oval Cells failed to differentiate into hepatocytes and underwent atypical ductular hyperplasia, exhibiting epithelial metaplasia and mucin production. Furthermore, changes in Wnt1 levels are required for the efficient regeneration of the liver by Oval Cells during massive hepatic injury.
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connective tissue growth factor with a novel fibronectin binding site promotes Cell adhesion and migration during rat Oval Cell activation
Hepatology, 2008Co-Authors: Xiaodong Ding, Marda Jorgensen, Jen Jung Pan, Dana G Pintilie, Alicia R Brown, Wenyuan Song, Bryon E PetersenAbstract:Oval Cell activation, as part of the regenerative process after liver injury, involves considerable Cell-matrix interaction. The matriCellular protein, connective tissue growth factor (CTGF), has been shown to be critical for Oval Cell activation during liver regeneration following N-2-acetylaminofluorene/partial hepatectomy. To understand the mode of action of CTGF during this process, N-terminal CTGF was used as bait to screen a yeast two-hybrid complementary DNA library specific for regenerating livers with massive Oval Cell presence. Fibronectin (FN), a prominent component of hepatic extraCellular matrix (ECM), was found to specifically bind to a new site on CTGF. In addition to module IV, this study showed that module I of CTGF was sufficient for binding to FN in both solid-phase in vitro binding assays and immunoprecipitation. Immunofluorescent staining revealed a dynamic ECM remodeling characterized by an FN-concentrated provisional matrix during Oval Cell–aided liver regeneration. Abundant CTGF protein was colocalized with FN in the provisional matrix. When expressed as recombinant proteins and immobilized on plastic surfaces, modules I and IV of CTGF were selectively adhesive to thymus Cell antigen 1–positive (Thy1+) Oval Cells, stellate Cells, and sinusoidal endothelial Cells but not to hepatocytes. The adhesion of these two modules on Thy1+ Oval Cells required heparan sulfate proteoglycan and integrin α5β1. Recombinant CTGF promoted an integrin α5β1–dependent migration but not proliferation on Thy1+ Oval Cells. Conclusion: Modules I and IV enabled the linkage of CTGF to FN and activated hepatic Cells. Through these bindings, CTGF on the FN-concentrated provisional matrix promoted Cell adhesion and migration, thereby facilitating Oval Cell activation. (HEPATOLOGY 2007.)
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bone marrow derived hepatic Oval Cells differentiate into hepatocytes in 2 acetylaminofluorene partial hepatectomy induced liver regeneration
Gastroenterology, 2007Co-Authors: Sehhoon Oh, Donghang Zheng, Rafal P Witek, Youngmi Jung, A C Piscaglia, Bryon E PetersenAbstract:Background & Aims: The ability of the bone marrow Cells to differentiate into liver, pancreas, and other tissues led to the speculation that these Cells might be the source of adult stem Cells found in these organs. The present study analyzed whether the bone marrow Cells are a source of hepatic Oval Cells involved in rat liver regeneration induced by 2-acetylaminofluorene (2-AAF) and 70% partial hepatectomy (PHx). Methods: Three groups of mutant F344 dipeptidyl peptidase IV–deficient (DPPIV−) rats were required for the study. Groups A and B received the mitotic inhibitor monocrotaline, followed by male F344 (DPPIV+) bone marrow transplantation. Next, group A received PHx only, while group B received the 2-AAF/PHx required for the Oval Cell activation. The last group C was used to analyze the effects of monocrotaline on transplanted bone marrow Cells. These rats underwent transplantation with bone marrow Cells and were then treated with monocrotaline. Subsequently, the animals were treated with 2-AAF/PHx. Results: In group A, DPPIV+ hepatocytes were found in the liver. Group B showed that approximately 20% of the Oval Cell population expressed both donor marker (DPPIV) and α-fetoprotein, and some differentiated into hepatocytes. In contrast, animals in group C failed to significantly induce Oval Cells with the donor DPPIV antigen. In addition, X/Y-chromosome analysis revealed that fusion was not contributing to differentiation of donor-derived Oval Cells. Conclusions: Our results suggest that under certain physiologic conditions, a portion of hepatic stem Cells might arise from the bone marrow and can differentiate into hepatocytes.
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role of connective tissue growth factor in Oval Cell response during liver regeneration after 2 aaf phx in rats
Gastroenterology, 2005Co-Authors: Thomas Shupe, Bryon E PetersenAbstract:Background & Aims: Recruitment and proliferation of Thy-1+ Oval Cells is a hallmark of liver regeneration after 2-acetylaminofluorene (2-AAF)/partial hepatectomy (PHx) in rats. To understand the molecular mechanism underlying this process, we investigated the role of connective tissue growth factor (CTGF), one of the candidate genes differentially expressed in Thy-1+ Oval Cells, in this liver injury model. Methods: Northern and Western analyses were performed to examine the induction of CTGF in total liver homogenate. Quantitative real-time polymerase chain reaction (PCR), immunofluorescent staining, and in situ hybridization were performed to confirm the expression and localization of CTGF in Thy-1+ Oval Cells. Finally, a known inhibitor of CTGF synthesis, Iloprost, was administered to 2-AAF/PHx treated rats to investigate the effect of Iloprost on Oval Cell response. Results: CTGF was found to be up-regulated at both the RNA and protein levels and occurred concurrently with an up-regulation of transforming growth factor β1 (TGF-β1). Sorted Thy-1+ Oval Cells expressed a high level of CTGF gene in a quantitative PCR assay. Colocalization of Thy-1 antigen and ctgf signals by in situ hybridization further confirmed that Thy-1+ Oval Cells were a source of CTGF. Iloprost administration blocked CTGF induction in treated animals but did not affect TGF-β1 expression. The inhibition of CTGF induction by Iloprost was associated with a significant decrease in Oval Cell proliferation and a lower level of α-fetoprotein expression as compared with control animals. Conclusions: These results show that CTGF induction is important for robust Oval Cell response after 2-AAF/PHx treatment in rats.
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hepatic Oval stem Cell in liver regeneration
Seminars in Cell & Developmental Biology, 2002Co-Authors: Heather M Hatch, Bryon E PetersenAbstract:Hepatic Oval Cell activation, proliferation, and differentiation has been observed under certain physiological conditions, mainly when the proliferation of existing hepatocytes has been inhibited followed by severe hepatic injury. Hepatic Oval Cells display a distinct phenotype and have been shown to be a bipotential progenitor of two types of epithelial Cells found in the liver, hepatocytes and bile ductular Cells. Bone marrow stem Cells have recently been shown to be a potential source of the hepatic Oval Cells and that reconstitution of an injured liver from a purified stem Cell population is possible. The focus of this review is on the studies involving the activation, proliferation, and differentiation of these hepatic Oval Cells and the role that they play in regeneration of the damaged liver. In order to present the potentiality of the hepatic Oval Cell, an experimental model that involves the inhibition of normal hepatic growth and division as well as severe hepatic injury via chemical or surgical means has been employed. In this model, an as yet undetermined signal or perhaps the lack of regenerative capability in the hepatocytes activates the hepatic Oval Cell compartment. However, other than understanding a potential origin of these Cells and some of the markers that characterize them, it still remains unclear as to how these Cells migrate ('home') into the damaged areas and how they begin their differentiation into mature and functioning hepatic Cells.
Belinda Knight - One of the best experts on this subject based on the ideXlab platform.
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attenuated liver progenitor Oval Cell and fibrogenic responses to the choline deficient ethionine supplemented diet in the balb c inbred strain of mice
Journal of Hepatology, 2007Co-Authors: Belinda Knight, Vance B Matthews, John K Olynyk, Lawrence J Abraham, Barbara Akhurst, Richard G Ruddell, Grant A Ramm, George C T YeohAbstract:Background/Aims Liver regeneration following chronic injury is associated with inflammation, the proliferation of liver progenitor (Oval) Cells and fibrosis. Previous studies identified interferon-gamma as a key mediator of Oval Cell proliferation. Interferon-γ is known to regulate Th1 Cell activities during immune challenge. Therefore, we hypothesised that progenitor Cell-mediated regeneration is associated with a Th1 immune response. Methods C57Bl/6 (normal Th1 response) and BALB/c mice (deficient in Th1 signalling) were placed on a carcinogenic diet to induce liver injury, progenitor Cell proliferation and fibrosis. Results Serum transaminases and mortality were elevated in BALB/c mice fed the diet. Proliferation of liver progenitor Cells was significantly attenuated in BALB/c animals. The pattern of cytokine expression and inflammation differed between strains. Liver fibrosis and hepatic stellate Cell activation were significantly inhibited in BALB/c mice compared to C57Bl/6. In addition, interferon-γ knockout mice also showed reduced fibrosis compared to wild type. These findings are in contrast to published results, in which interferon-gamma is shown to be anti-fibrogenic. Conclusions Our data demonstrate that the hepatic progenitor Cell response to a CDE diet is inhibited in mice lacking Th1 immune signalling and further show that this inhibition is associated with reduced liver fibrosis.
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transforming growth factor beta differentially regulates Oval Cell and hepatocyte proliferation
Hepatology, 2007Co-Authors: Lananh N Nguyen, Belinda Knight, George C T Yeoh, Nelson Fausto, Jean S Campbell, Momoko H Furuya, Lawrence A Wolfraim, Anthony P Nguyen, Matthew S Holdren, Tony W ParksAbstract:Oval Cells are hepatocytic precursors that proliferate in late-stage cirrhosis and that give rise to a subset of human hepatoCellular carcinomas. Although liver regeneration typically occurs through replication of existing hepatocytes, Oval Cells proliferate only when hepatocyte proliferation is inhibited. Transforming growth factor-β (TGF-β) is a key inhibitory cytokine for hepatocytes, both in vitro and in vivo. Because TGF-β levels are elevated in chronic liver injury when Oval Cells arise, we hypothesized that Oval Cells may be less responsive to the growth inhibitory effects of this cytokine. To examine TGF-β signaling in vivo in Oval Cells, we analyzed livers of rats fed a choline-deficient, ethionine-supplemented (CDE) diet for phospho-Smad2. Phospho-Smad2 was detected in more than 80% of hepatocytes, but staining was substantially reduced in Oval Cells. Ki67 staining, in contrast, was significantly more common in Oval Cells than hepatocytes. To understand the inverse relationship between TGF-β signaling and proliferation in Oval Cells and hepatocytes, we examined TGF-β signaling in vitro. TGF-β caused marked growth inhibition in primary hepatocytes and the AML12 hepatocyte Cell line. Two Oval Cell lines, LE/2 and LE/6, were less responsive. The greater sensitivity of the hepatocytes to TGF-β–induced growth inhibition may result from the absence of Smad6 in these Cells. Conclusion: Our results indicate that Oval Cells, both in vivo and in vitro, are less sensitive to TGF-β–induced growth inhibition than hepatocytes. These findings further suggest an underlying mechanism for the proliferation of Oval Cells in an environment inhibitory to hepatocytic proliferation. (HEPATOLOGY 2007;45:31–41.)
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liver inflammation and cytokine production but not acute phase protein synthesis accompany the adult liver progenitor Oval Cell response to chronic liver injury
Immunology and Cell Biology, 2005Co-Authors: Belinda Knight, Vance B Matthews, John K Olynyk, Lawrence J Abraham, Barbara Akhurst, Emma J Croager, Elizabeth Klinken, George C T YeohAbstract:Oval Cells are facultative liver progenitor Cells, which are invoked during chronic liver injury in order to replenish damaged hepatocytes and bile duct Cells. Previous studies have observed inflammation and cytokine production in the liver during chronic injury. Further, it has been proposed that inflammatory growth factors may mediate the proliferation of Oval Cells during disease progression. We have undertaken a detailed examination of inflammation and cytokine production during a time course of liver injury and repair, invoked by feeding mice a choline-deficient, ethionine-supplemented (CDE) diet. We show that immediately following initial liver injury, B220-expressing leucocytes transiently infiltrate the liver. This inflammatory response occurred immediately before Oval Cell numbers began to expand in the liver, suggesting that the two events may be linked. Two waves of liver cytokine production were observed during the CDE time course. The first occurred shortly following commencement of the diet, suggesting that it may represent a hepatic acute phase response. However, examination of acute phase marker expression in CDE-fed mice did not support this hypothesis. The second wave of cytokine expression correlated with the expansion of Oval Cell numbers in the liver, suggesting that these factors may mediate Oval Cell proliferation. No inflammatory signalling was detected following withdrawal of the injury stimulus. In summary, our results document a close correlation between inflammation, cytokine production and the expansion of Oval Cells in the liver during experimental chronic injury.
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oncostatin m induces an acute phase response but does not modulate the growth or maturation status of liver progenitor Oval Cells in culture
Experimental Cell Research, 2005Co-Authors: Vance B Matthews, Belinda Knight, Janina E E Tirnitzparker, James Boon, John K Olynyk, George C T YeohAbstract:Following acute injury, the liver regenerates through hepatocyte division. If this pathway is impaired, liver repair depends on the recruitment of adult liver progenitor (Oval) Cells. Mice fed a choline deficient, ethionine supplemented (CDE) diet possess substantial numbers of Oval Cells, which can be isolated, or examined in vivo. Oncostatin M (OSM) has been shown to induce maturation of murine fetal hepatoblasts into hepatocytes. We recently confirmed this in human fetal liver cultures. Here, we show that liver OSM expression increases in mice fed a CDE diet and CDE-derived Oval Cell isolates express OSM and its receptor (OSMR). Oval Cell lines (PIL Cells), as well as primary Oval Cell cultures, displayed STAT-3 phosphorylation following OSM stimulation. OSM had no effect on the growth of primary Oval Cells, but it was pro-apoptotic to PIL Cells, suggesting that the two Cell models are not directly comparable. Expression of PCNA and cyclin D1 was not affected by OSM treatment. No evidence was obtained to suggest an effect on Oval Cell maturation with OSM treatment. However, decreased albumin production, accompanied by increased expression of haptoglobin and fibrinogen, suggests that OSM induced an acute phase reaction in cultured Oval Cells.
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impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice
Journal of Experimental Medicine, 2000Co-Authors: Belinda Knight, George C T Yeoh, Kirsten L Husk, Lawrence J Abraham, Jonathan A Rhim, Nelson FaustoAbstract:Hepatic stem Cells (Oval Cells) proliferate within the liver after exposure to a variety of hepatic carcinogens and can generate both hepatocytes and bile duct Cells. Oval Cell proliferation is commonly seen in the preneoplastic stages of liver carcinogenesis, often accompanied by an inflammatory response. Tumor necrosis factor (TNF), an inflammatory cytokine, is also important in liver regeneration and hepatoCellular growth. The experiments reported here explore the relationship among the TNF inflammatory pathway, liver stem Cell activation, and tumorigenesis. We demonstrate that TNF is upregulated during Oval Cell proliferation induced by a choline-deficient, ethionine-supplemented diet and that it is expressed by Oval Cells. In TNF receptor type 1 knockout mice, Oval Cell proliferation is substantially impaired and tumorigenesis is reduced. Oval Cell proliferation is impaired to a lesser extent in interleukin 6 knockout mice and is unchanged in TNF receptor type 2 knockout mice. These findings demonstrate that TNF signaling participates in the proliferation of Oval Cells during the preneoplastic phase of liver carcinogenesis and that loss of signaling through the TNF receptor type 1 reduces the incidence of tumor formation. The TNF inflammatory pathway may be a target for therapeutic intervention during the early stages of liver carcinogenesis.
Snorri S Thorgeirsson - One of the best experts on this subject based on the ideXlab platform.
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reconstitution of liver mass via Cellular hypertrophy in the rat
Hepatology, 2001Co-Authors: Peter Nagy, Tadahisa Teramoto, Valentina M Factor, Aranzazu Sanchez, Janos Schnur, Sandor Paku, Snorri S ThorgeirssonAbstract:The liver has an extremely effective regenerative capacity. When 70% of a rat liver is removed by surgery, the liver mass regrows in 7 to 10 days by the compensatory hyperplasia of the remnant part. In case of damage to the surviving hepatocytes, the facultative stem-Cell compartment is activated and the liver regenerates by means of Oval-Cell proliferation/differentiation. In the present study, we demonstrate that when both hepatocyte proliferation and stem-Cell activation were prevented by dexamethasone (Dex) administration, the liver mass was restored in the absence of DNA synthesis. The restoration of the liver was accomplished by the preferential enlargement/hypertrophy of the periportal hepatocytes. A similar response was observed when Cell proliferation was arrested by 5-fluorouracil (FU) following partial hepatectomy. Therefore, the hepatocytic hypertrophy appears to provide an alternative mechanism of liver-mass restoration. This hypertrophic condition of the liver is not stable, because following the withdrawal of Dex, the enlarged hepatocytes entered in the Cell cycle and the normal liver structure and DNA content was re-established.
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atypical ductular proliferation and its inhibition by transforming growth factor beta1 in the 3 5 diethoxycarbonyl 1 4 dihydrocollidine mouse model for chronic alcoholic liver disease
Laboratory Investigation, 1999Co-Authors: K H Preisegger, V M Factor, Andrea Fuchsbichler, C Stumptner, H Denk, Snorri S ThorgeirssonAbstract:Many acute and chronic liver diseases are often associated with atypical ductular proliferation (ADP). These ADPs have gained increasing interest since a number of recent observations suggest that ADPs may represent progenies of the putative liver stem Cell compartment. In this study, we show that feeding mice with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) results in persistent proliferation of primitive ductules with poorly defined lumens. Similar to Oval Cell proliferation in other rodent models as well as in various human liver diseases, DDC-induced ADP originated from the portal tract, spread into the hepatic lobule, and was associated closely with appearance of hepatocytes harboring an antigen (A6), which normally is expressed in biliary epithelium. Furthermore, DDC treatment severely inhibited the regenerative capacity of mice after partial hepatectomy. The development of ADP was selectively blocked in DDC-fed TGF-beta1 transgenic mice producing active TGF-beta1 in the liver and no accumulation of new hepatocytes expressing the A6 antigen was observed. Moreover, the transforming growth factor beta1 (TGF-beta1) transgenic mice did not survive beyond 3 weeks from starting the DDC-containing diet. The results suggest that persistent activation of the hepatic stem Cell compartment is essential for liver regeneration in the DDC model and that active TGF-beta1 may negatively control activation of stem Cells in the liver. These data further emphasize the relevance of the DDC model as an experimental tool for studying chronic liver diseases.
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wholesale hepatocytic differentiation in the rat from ductular Oval Cells the progeny of biliary stem Cells
Journal of Hepatology, 1997Co-Authors: Malcolm R Alison, El-nasir Lalani, Matthew Golding, Peter Nagy, Snorri S Thorgeirsson, Catherine SarrafAbstract:Abstract Background/Aims: Biliary epithelial Cells (ductular Oval Cells) migrate into the periportal and midzonal parenchyma when hepatocyte regeneration after injury is significantly impeded. The potential of Oval Cells to differentiate into hepatocytes has been questioned. We have sought to resolve this issue using the modified Solt-Farber procedure in which 2-acetylaminofluorene is used to block hepatocyte regeneration in partially hepatectomized rats. Methods: Rats received 2-acetylaminofluoren by oral gavage for 6 days before and up to 7 days after a two-thirds hepatectomy. The Cellular reaction was visualized by the immunohistochemical localization of intermediate filaments cytokeratins 8 and 19 and vimentin, cytochrome P450 enzymatic proteins and α-foetoprotein. Expression of albumin and α-foetoprotein mRNA transcripts were observed in situ using antisense riboprobes. Results: During the first 9 days after partial hepatectomy long strings of ductural Cells spread outwards from the portal areas. These Cells exhibited strong diffuse cytoplasmic staining with the anticytokeratin 8 and 19 antibodies, like authentic bile ducts, but in addition also expressed vimentin and α-foetoprotein (protein and mRNA) — collectively termed the "Oval Cell phenotype". Thereafter, these ducts rapidly vanished to be replaced by basophilic hepatocytes which lacked the Oval Cell phenotype, but which acquired strong expression of albumin mRNA. At 14 days after partial hepatectomy the Oval Cell phenotype was restricted to the peripheral margins of the newborn periportal hepatocytes, the distal tips of the Ovall Cell ducts, and these too had disappeared within another 7 days. Conclusions: Ductural Oval Cells with differentiate into hepatocytes under appropriate experimental conditions.
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modulation of keratin 14 and α fetoprotein expression during hepatic Oval Cell proliferation and liver regeneration
Journal of Cellular Physiology, 1994Co-Authors: Hanne Cathrine Bisgaard, Peter Phuongnga Nagy T Ton, Snorri S ThorgeirssonAbstract:Keratin 14 (K14) expression has recently been demonstrated in Cell lines of non-parenchymal hepatic origin (Bisgaard et al., 1993, Mol. Carcinog., 7:60–66; Bisgaard et al., 1991, J. Cell. Physiol., 147:333–343). These Cell lines are thought to represent a progeny of a dormant stem Cell compartment present in the adult rat liver, which may participate in the restoration of the liver mass after experimental liver injury. Utilizing a combination of 2-acetylaminofluorene (2-AAF) administration and partial hepatectomy to activate liver regeneration by proliferation of Oval Cells, we examined the modulation of K14 as well as α-fetoprotein (AFP) expression in proliferating Oval Cells and lineages hypothesized to be derived herefrom. We showed by Northern blot and in situ hybridization analyses that K14 and AFP transcripts were initially accumulating in epithelial Cells located in subsets of ductal structures in the portal areas. As Oval Cells infiltrated the liver parenchyma, K14 transcripts were detected in Oval Cells, in foci of small basophilic hepatocytes, and in structures resembling glandular intestinal-type epithelium. AFP was expressed in Oval Cells, and at low but detectable levels in foci of basophilic hepatocytes, but not in glandular intestinal-type epithelium. Neither K14 nor AFP transcripts were detected in bile ducts or mature hepatocytes at any time during Oval Cell proliferation and reconstitution of the liver mass. To further study the modulation of K14 and AFP expression we utilized an in vitro model in which spontaneous transformation of rat liver epithelial (RLE) Cells appeared to mimic the process of early differentiation along the hepatic lineage in vivo. We demonstrated that undifferentiated RLE Cells at a late passage expressed K14 and vimentin, whereas transformation and differentiation to hepatoblast-like progeny resulted in an abrogation of K14 and vimentin expression and an induction of K18 and AFP. We propose that K14 and AFP are sequentially modulated in subpopulations of Oval Cells involved in the ongoing reconstitution of the liver mass. © 1994 wiley-Liss, Inc.
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expression of stem Cell factor and its receptor c kit during liver regeneration from putative stem Cells in adult rat
Laboratory Investigation, 1994Co-Authors: Kozo Fujio, R P Evarts, Elizabeth R Marsden, Snorri S ThorgeirssonAbstract:Background Stem Cell factor (SCF) and its receptor, c-kit, are known to play important roles in hematopoiesis, melanogenesis, and gametogenesis. The biologic effects of the SCF/c-kit system are believed to involve survival, proliferation, and migration of early stem Cell progeny. Although SCF and c-kit receptor are widely expressed during normal embryonic development, their expression in the adult is limited. Experimental design The expression of SCF and c-kit genes was examined during liver regeneration via the Oval Cell compartment utilizing partial hepatectomy (PH) combined with the administration of a noncarcinogenic dose of 2-acetylaminofluorene (AAF) for 8 days (AAF/PH model). Results Both the ligand and the receptor genes were expressed during the early stages of Oval Cell proliferation after partial hepatectomy in the AAF/PH model, while neither simple partial hepatectomy nor AAF administration alone induced a noticeable expression of the SCF/c-kit system. The level of SCF mRNA increased within 12 hours after partial hepatectomy and reached a peak around day 4. Thus, the expression of SCF preceded the major expansion of the Oval Cell compartment. The level of c-kit transcripts gradually increased from the 12-hour time point and stayed elevated until day 11, when a large proportion of the Oval Cells differentiated into small basophilic hepatocytes. Separation of liver Cells at day 3 in the AAF/PH model into parenchymal and nonparenchymal fractions demonstrated that the expression of both SCF and c-kit receptor genes was restricted to the nonparenchymal Cells. Furthermore, in situ hybridization revealed that the c-kit transcripts were restricted to Oval Cells, whereas the SCF transcripts were expressed in both Oval Cells and Ito Cells. Conclusions The transcripts for the c-kit receptor are expressed in the early progeny of the hepatic stem Cells. The SCF/c-kit system may, possibly in combination with other growth factor/receptor systems, be involved in the early activation of the hepatic stem Cells as well as in the expansion and differentiation of Oval Cells.
Lawrence J Abraham - One of the best experts on this subject based on the ideXlab platform.
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attenuated liver progenitor Oval Cell and fibrogenic responses to the choline deficient ethionine supplemented diet in the balb c inbred strain of mice
Journal of Hepatology, 2007Co-Authors: Belinda Knight, Vance B Matthews, John K Olynyk, Lawrence J Abraham, Barbara Akhurst, Richard G Ruddell, Grant A Ramm, George C T YeohAbstract:Background/Aims Liver regeneration following chronic injury is associated with inflammation, the proliferation of liver progenitor (Oval) Cells and fibrosis. Previous studies identified interferon-gamma as a key mediator of Oval Cell proliferation. Interferon-γ is known to regulate Th1 Cell activities during immune challenge. Therefore, we hypothesised that progenitor Cell-mediated regeneration is associated with a Th1 immune response. Methods C57Bl/6 (normal Th1 response) and BALB/c mice (deficient in Th1 signalling) were placed on a carcinogenic diet to induce liver injury, progenitor Cell proliferation and fibrosis. Results Serum transaminases and mortality were elevated in BALB/c mice fed the diet. Proliferation of liver progenitor Cells was significantly attenuated in BALB/c animals. The pattern of cytokine expression and inflammation differed between strains. Liver fibrosis and hepatic stellate Cell activation were significantly inhibited in BALB/c mice compared to C57Bl/6. In addition, interferon-γ knockout mice also showed reduced fibrosis compared to wild type. These findings are in contrast to published results, in which interferon-gamma is shown to be anti-fibrogenic. Conclusions Our data demonstrate that the hepatic progenitor Cell response to a CDE diet is inhibited in mice lacking Th1 immune signalling and further show that this inhibition is associated with reduced liver fibrosis.
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liver inflammation and cytokine production but not acute phase protein synthesis accompany the adult liver progenitor Oval Cell response to chronic liver injury
Immunology and Cell Biology, 2005Co-Authors: Belinda Knight, Vance B Matthews, John K Olynyk, Lawrence J Abraham, Barbara Akhurst, Emma J Croager, Elizabeth Klinken, George C T YeohAbstract:Oval Cells are facultative liver progenitor Cells, which are invoked during chronic liver injury in order to replenish damaged hepatocytes and bile duct Cells. Previous studies have observed inflammation and cytokine production in the liver during chronic injury. Further, it has been proposed that inflammatory growth factors may mediate the proliferation of Oval Cells during disease progression. We have undertaken a detailed examination of inflammation and cytokine production during a time course of liver injury and repair, invoked by feeding mice a choline-deficient, ethionine-supplemented (CDE) diet. We show that immediately following initial liver injury, B220-expressing leucocytes transiently infiltrate the liver. This inflammatory response occurred immediately before Oval Cell numbers began to expand in the liver, suggesting that the two events may be linked. Two waves of liver cytokine production were observed during the CDE time course. The first occurred shortly following commencement of the diet, suggesting that it may represent a hepatic acute phase response. However, examination of acute phase marker expression in CDE-fed mice did not support this hypothesis. The second wave of cytokine expression correlated with the expansion of Oval Cell numbers in the liver, suggesting that these factors may mediate Oval Cell proliferation. No inflammatory signalling was detected following withdrawal of the injury stimulus. In summary, our results document a close correlation between inflammation, cytokine production and the expansion of Oval Cells in the liver during experimental chronic injury.
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hepatic expression of the tumor necrosis factor family member lymphotoxin beta is regulated by interleukin il 6 and il 1beta transcriptional control mechanisms in Oval Cells and hepatoma Cell lines
Liver International, 2005Co-Authors: Lily S Subrata, John K Olynyk, George C T Yeoh, Kim N Lowes, Elizabeth Quail, Lawrence J AbrahamAbstract:Background: Lymphotoxin-β (LT-β) plays an important role in inflammation and its promoter contains a functional nuclear factor-κB (NF-κB) element, rendering it a likely target of pro-inflammatory cytokines. Inflammatory cytokines play a central role in liver regeneration resulting from acute or chronic liver injury, with interleukin (IL)-6 signaling essential for liver regeneration induced by partial hepatectomy. In hepatic Oval Cells observed following chronic liver injury, LT-β levels are upregulated, suggesting a link between LT-β and liver regeneration. Results: The expression of LT-β in hepatic Oval Cell and hepatoCellular carcinoma Cell lines was further investigated, along with its responsiveness to IL-6 and IL-1β. Key regulatory cis-acting elements of the LT-β promoter that mediate IL-6 responsiveness (Sp/BKLF, Ets, NF-κB and Egr-1/Sp1) and IL-1β responsiveness (NF-κB and Ets) of hepatic LT-β expression were identified. The novel binding of basic Kruppel-like factor (BKLF) proteins to an apparent composite Sp/BKLF site of the LT-β promoter was shown to mediate IL-6 responsiveness. Binding of NF-κB p65/p50 heterodimers and Ets-related transcription factors to their respective sites mediates responsiveness to IL-1β. Conclusion: The identification of IL-6 and IL-1β as activators of LT-β supports their involvement in LT-β signaling in liver regeneration associated with chronic liver damage.
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differential lymphotoxin β and interferon gamma signaling during mouse liver regeneration induced by chronic and acute injury
Hepatology, 2005Co-Authors: Barbara Akhurst, Vance B Matthews, Kirsten L Husk, Lawrence J Abraham, Mark J Smyth, George C T YeohAbstract:The liver regenerates after acute injury via hepatocyte Cell division; during chronic injury, when hepatocyte replication is impaired or blocked, liver progenitor Oval Cells mediate liver regeneration. If both regeneration options are blocked in animal models, then liver failure and death ensues. The mechanisms underlying Oval Cell induction, proliferation, and subsequent liver regeneration remain poorly characterized. In particular, Cell-signaling pathways that distinguish the alternative pathways are unknown. This study shows that in a mouse model, hepatic expression of lymphotoxin-beta (LTbeta) and interferon gamma (IFNgamma) transcripts is increased in response to the choline-deficient, ethionine-supplemented (CDE) diet, which induces Oval Cell-mediated liver regeneration. Oval Cells express LTbeta and IFNgamma transcripts, contributing to the increased expression in the liver of mice fed the CDE diet. An attenuated Oval Cell response to such a diet was observed in LTbeta receptor-, LTbeta-, and IFNgamma-gene targeted mice. Loss of LTbeta and LTbeta receptor signaling reduced the number of Oval Cells expressing A6 and muscle pyruvate kinase. The lack of IFNgamma signaling reduced muscle pyruvate kinase(+), but not A6(+), Oval Cells. In contrast, partial hepatectomy suppressed LTbeta and IFNgamma transcripts. We also show that IFNgamma induces STAT-3 phosphorylation in an Oval Cell line. In conclusion, LTbeta, LTbeta receptor, and IFNgamma are involved in Oval Cell-mediated, but not hepatocyte-mediated, liver regeneration, and the absence of these pathways impairs the Oval Cell-dependent regenerative response.
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impaired preneoplastic changes and liver tumor formation in tumor necrosis factor receptor type 1 knockout mice
Journal of Experimental Medicine, 2000Co-Authors: Belinda Knight, George C T Yeoh, Kirsten L Husk, Lawrence J Abraham, Jonathan A Rhim, Nelson FaustoAbstract:Hepatic stem Cells (Oval Cells) proliferate within the liver after exposure to a variety of hepatic carcinogens and can generate both hepatocytes and bile duct Cells. Oval Cell proliferation is commonly seen in the preneoplastic stages of liver carcinogenesis, often accompanied by an inflammatory response. Tumor necrosis factor (TNF), an inflammatory cytokine, is also important in liver regeneration and hepatoCellular growth. The experiments reported here explore the relationship among the TNF inflammatory pathway, liver stem Cell activation, and tumorigenesis. We demonstrate that TNF is upregulated during Oval Cell proliferation induced by a choline-deficient, ethionine-supplemented diet and that it is expressed by Oval Cells. In TNF receptor type 1 knockout mice, Oval Cell proliferation is substantially impaired and tumorigenesis is reduced. Oval Cell proliferation is impaired to a lesser extent in interleukin 6 knockout mice and is unchanged in TNF receptor type 2 knockout mice. These findings demonstrate that TNF signaling participates in the proliferation of Oval Cells during the preneoplastic phase of liver carcinogenesis and that loss of signaling through the TNF receptor type 1 reduces the incidence of tumor formation. The TNF inflammatory pathway may be a target for therapeutic intervention during the early stages of liver carcinogenesis.
