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  1. Article ; Online: An Elf2-like transcription factor acts as repressor of the mouse ecto-5'-nucleotidase gene expression in hepatic myofibroblasts.

    Fausther, Michel / Lavoie, Elise G / Goree, Jessica R / Dranoff, Jonathan A

    Purinergic signalling

    2017  Volume 13, Issue 4, Page(s) 417–428

    Abstract: Hepatic fibrosis represents a pathological wound healing and tissue repair process triggered in response to chronic liver injury. A heterogeneous population of activated non-parenchymal liver cells, known as liver myofibroblasts, functions as the ... ...

    Abstract Hepatic fibrosis represents a pathological wound healing and tissue repair process triggered in response to chronic liver injury. A heterogeneous population of activated non-parenchymal liver cells, known as liver myofibroblasts, functions as the effector cells in hepatic fibrosis. Upon activation, liver myofibroblasts become fibrogenic, acquiring contractile properties and increasing collagen production capacity, while developing enhanced sensitivity to endogenous molecules and factors released in the local microenvironment. Hepatic extracellular adenosine is a bioactive small molecule, increasingly recognized as an important regulator of liver myofibroblast functions, and an important mediator in the pathogenesis of liver fibrosis overall. Remarkably, ecto-5'-nucleotidase/Nt5e/Cd73 enzyme, which accounts for the dominant adenosine-generating activity in the extracellular medium, is expressed by activated liver myofibroblasts. However, the molecular signals regulating Nt5e gene expression in liver myofibroblasts remain poorly understood. Here, we show that activated mouse liver myofibroblasts express Nt5e gene products and characterize the putative Nt5e minimal promoter in the mouse species. We describe the existence of an enhancer sequence upstream of the mouse Nt5e minimal promoter and establish that the mouse Nt5e minimal promoter transcriptional activity is negatively regulated by an Elf2-like Ets-related transcription factor in activated mouse liver myofibroblasts.
    MeSH term(s) 5'-Nucleotidase/biosynthesis ; Animals ; DNA-Binding Proteins/metabolism ; Gene Expression Regulation/physiology ; Liver Cirrhosis/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Myofibroblasts/metabolism ; Transcription Factors/metabolism
    Chemical Substances DNA-Binding Proteins ; Elf2 protein, mouse ; Transcription Factors ; 5'-Nucleotidase (EC 3.1.3.5)
    Language English
    Publishing date 2017-06-30
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2172143-9
    ISSN 1573-9546 ; 1573-9538
    ISSN (online) 1573-9546
    ISSN 1573-9538
    DOI 10.1007/s11302-017-9570-7
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Expression of mediators of purinergic signaling in human liver cell lines.

    Goree, Jessica R / Lavoie, Elise G / Fausther, Michel / Dranoff, Jonathan A

    Purinergic signalling

    2014  Volume 10, Issue 4, Page(s) 631–638

    Abstract: Purinergic signaling regulates a diverse and biologically relevant group of processes in the liver. However, progress of research into functions regulated by purinergic signals in the liver has been hampered by the complexity of systems probed. ... ...

    Abstract Purinergic signaling regulates a diverse and biologically relevant group of processes in the liver. However, progress of research into functions regulated by purinergic signals in the liver has been hampered by the complexity of systems probed. Specifically, there are multiple liver cell subpopulations relevant to hepatic functions, and many of these have been effectively modeled in human cell lines. Furthermore, there are more than 20 genes relevant to purinergic signaling, each of which has distinct functions. Hence, we felt the need to categorize genes relevant to purinergic signaling in the best characterized human cell line models of liver cell subpopulations. Therefore, we investigated the expression of adenosine receptor, P2X receptor, P2Y receptor, and ecto-nucleotidase genes via RT-PCR in the following cell lines: LX-2, hTERT, FH11, HepG2, Huh7, H69, and MzChA-1. We believe that our findings will provide an excellent resource to investigators seeking to define functions of purinergic signals in liver physiology and liver disease pathogenesis.
    MeSH term(s) Adenosine Triphosphatases/metabolism ; Cell Line ; Hepatic Stellate Cells/metabolism ; Hepatocytes/metabolism ; Humans ; Liver/cytology ; Liver/metabolism ; Purines/metabolism ; Receptors, Purinergic P1/metabolism ; Receptors, Purinergic P2X/metabolism ; Receptors, Purinergic P2Y/metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/physiology
    Chemical Substances Purines ; Receptors, Purinergic P1 ; Receptors, Purinergic P2X ; Receptors, Purinergic P2Y ; Adenosine Triphosphatases (EC 3.6.1.-) ; ectoATPase (EC 3.6.1.-)
    Language English
    Publishing date 2014-09-07
    Publishing country Netherlands
    Document type Journal Article
    ZDB-ID 2172143-9
    ISSN 1573-9546 ; 1573-9538
    ISSN (online) 1573-9546
    ISSN 1573-9538
    DOI 10.1007/s11302-014-9425-4
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Establishment and characterization of rat portal myofibroblast cell lines.

    Fausther, Michel / Goree, Jessica R / Lavoie, Élise G / Graham, Alicia L / Sévigny, Jean / Dranoff, Jonathan A

    PloS one

    2015  Volume 10, Issue 3, Page(s) e0121161

    Abstract: The major sources of scar-forming myofibroblasts during liver fibrosis are activated hepatic stellate cells (HSC) and portal fibroblasts (PF). In contrast to well-characterized HSC, PF remain understudied and poorly defined. This is largely due to the ... ...

    Abstract The major sources of scar-forming myofibroblasts during liver fibrosis are activated hepatic stellate cells (HSC) and portal fibroblasts (PF). In contrast to well-characterized HSC, PF remain understudied and poorly defined. This is largely due to the facts that isolation of rodent PF for functional studies is technically challenging and that PF cell lines had not been established. To address this, we have generated two polyclonal portal myofibroblast cell lines, RGF and RGF-N2. RGF and RGF-N2 were established from primary PF isolated from adult rat livers that underwent culture activation and subsequent SV40-mediated immortalization. Specifically, Ntpdase2/Cd39l1-sorted primary PF were used to generate the RGF-N2 cell line. Both cell lines were functionally characterized by RT-PCR, immunofluorescence, immunoblot and bromodeoxyuridine-based proliferation assay. First, immortalized RGF and RGF-N2 cells are positive for phenotypic myofibroblast markers alpha smooth muscle actin, type I collagen alpha-1, tissue inhibitor of metalloproteinases-1, PF-specific markers elastin, type XV collagen alpha-1 and Ntpdase2/Cd39l1, and mesenchymal cell marker ecto-5'-nucleotidase/Cd73, while negative for HSC-specific markers desmin and lecithin retinol acyltransferase. Second, both RGF and RGF-N2 cell lines are readily transfectable using standard methods. Finally, RGF and RGF-N2 cells attenuate the growth of Mz-ChA-1 cholangiocarcinoma cells in co-culture, as previously demonstrated for primary PF. Immortalized rat portal myofibroblast RGF and RGF-N2 cell lines express typical markers of activated PF-derived myofibroblasts, are suitable for DNA transfection, and can effectively inhibit cholangiocyte proliferation. Both RGF and RGF-N2 cell lines represent novel in vitro cellular models for the functional studies of portal (myo)fibroblasts and their contribution to the progression of liver fibrosis.
    MeSH term(s) Animals ; Biomarkers/metabolism ; Bromodeoxyuridine ; Cell Culture Techniques/methods ; Cell Line ; Fluorescent Antibody Technique ; Immunoblotting ; Liver/cytology ; Myofibroblasts/cytology ; Myofibroblasts/physiology ; Portal System/cytology ; Rats ; Reverse Transcriptase Polymerase Chain Reaction
    Chemical Substances Biomarkers ; Bromodeoxyuridine (G34N38R2N1)
    Language English
    Publishing date 2015-03-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0121161
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: NT5E mutations that cause human disease are associated with intracellular mistrafficking of NT5E protein.

    Fausther, Michel / Lavoie, Elise G / Goree, Jessica R / Baldini, Giulia / Dranoff, Jonathan A

    PloS one

    2014  Volume 9, Issue 6, Page(s) e98568

    Abstract: Ecto-5'-nucleotidase/CD73/NT5E, the product of the NT5E gene, is the dominant enzyme in the generation of adenosine from degradation of AMP in the extracellular environment. Nonsense (c.662C→A, p.S221X designated F1, c.1609dupA, p.V537fsX7 designated F3) ...

    Abstract Ecto-5'-nucleotidase/CD73/NT5E, the product of the NT5E gene, is the dominant enzyme in the generation of adenosine from degradation of AMP in the extracellular environment. Nonsense (c.662C→A, p.S221X designated F1, c.1609dupA, p.V537fsX7 designated F3) and missense (c.1073G→A, p.C358Y designated F2) NT5E gene mutations in three distinct families have been shown recently to cause premature arterial calcification disease in human patients. However, the underlying mechanisms by which loss-of-function NT5E mutations cause human disease are unknown. We hypothesized that human NT5E gene mutations cause mistrafficking of the defective proteins within cells, ultimately blocking NT5E catalytic function. To test this hypothesis, plasmids encoding cDNAs of wild type and mutant human NT5E tagged with the fluorescent probe DsRed were generated and used for transfection and heterologous expression in immortalized monkey COS-7 kidney cells that lack native NT5E protein. Enzyme histochemistry and Malachite green assays were performed to assess the biochemical activities of wild type and mutant fusion NT5E proteins. Subcellular trafficking of fusion NT5E proteins was monitored by confocal microscopy and western blot analysis of fractionated cell constituents. All 3 F1, F2, and F3 mutations result in a protein with significantly reduced trafficking to the plasma membrane and reduced ER retention as compared to wild type protein. Confocal immunofluorescence demonstrates vesicles containing DsRed-tagged NT5E proteins (F1, F2 and F3) in the cell synthetic apparatus. All 3 mutations resulted in absent NT5E enzymatic activity at the cell surface. In conclusion, three familial NT5E mutations (F1, F2, F3) result in novel trafficking defects associated with human disease. These novel genetic causes of human disease suggest that the syndrome of premature arterial calcification due to NT5E mutations may also involve a novel "trafficking-opathy".
    MeSH term(s) 5'-Nucleotidase/genetics ; Animals ; COS Cells ; Chlorocebus aethiops ; GPI-Linked Proteins/genetics ; Humans ; Mutation
    Chemical Substances GPI-Linked Proteins ; 5'-Nucleotidase (EC 3.1.3.5) ; NT5E protein, human (EC 3.1.3.5)
    Language English
    Publishing date 2014-06-02
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0098568
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: MCP-1 downregulates MMP-9 export via vesicular redistribution to lysosomes in rat portal fibroblasts.

    Hickman, DaShawn A / Syal, Gaurav / Fausther, Michel / Lavoie, Elise G / Goree, Jessica R / Storrie, Brian / Dranoff, Jonathan A

    Physiological reports

    2014  Volume 2, Issue 11

    Abstract: Portal fibroblasts (PF) are one of the two primary cell types contributing to the myofibroblast population of the liver and are thus essential to the pathogenesis of liver fibrosis. Monocyte chemoattractant protein-1 (MCP-1) is a known profibrogenic ... ...

    Abstract Portal fibroblasts (PF) are one of the two primary cell types contributing to the myofibroblast population of the liver and are thus essential to the pathogenesis of liver fibrosis. Monocyte chemoattractant protein-1 (MCP-1) is a known profibrogenic chemokine that may be of particular importance in biliary fibrosis. We examined the effect of MCP-1 on release of matrix metalloproteinase-9 (MMP-9) by rat PF. We found that MCP-1 blocks PF release of MMP-9 in a posttranslational fashion. We employed an optical and electron microscopic approach to determine the mechanism of this downregulation. Our data demonstrated that, in the presence of MCP-1, MMP-9-containing vesicles were shunted to a lysosome-like compartment. This is the first report of a secretory protein to be so regulated in fibrogenic cells.
    Language English
    Publishing date 2014-11-01
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2724325-4
    ISSN 2051-817X
    ISSN 2051-817X
    DOI 10.14814/phy2.12153
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  6. Article ; Online: Pathological changes in pulmonary circulation in carbon tetrachloride (CCl4)-induced cirrhotic mice.

    Das, Mita / Boerma, Marjan / Goree, Jessica R / Lavoie, Elise G / Fausther, Michel / Gubrij, Igor B / Pangle, Amanda K / Johnson, Larry G / Dranoff, Jonathan A

    PloS one

    2014  Volume 9, Issue 4, Page(s) e96043

    Abstract: Rationale: Lack of an experimental model of portopulmonary hypertension (POPH) has been a major obstacle in understanding of pathophysiological mechanisms underlying the disease.: Objective: We investigated the effects of CCl4-mediated cirrhosis on ... ...

    Abstract Rationale: Lack of an experimental model of portopulmonary hypertension (POPH) has been a major obstacle in understanding of pathophysiological mechanisms underlying the disease.
    Objective: We investigated the effects of CCl4-mediated cirrhosis on the pulmonary vasculature, as an initial step towards an improved understanding of POPH.
    Methods and results: Male C57BL/6 mice received intraperitoneal injection of either sterile olive oil or CCl4 3 times/week for 12 weeks. Cirrhosis and portal hypertension were confirmed by evidence of bridging fibrosis and nodule formation in CCl4-treated liver determined by trichrome/picrosirius red staining and an increase in spleen weight/body weight ratio, respectively. Staining for the oxidative stress marker, 4-hydroxynonenal (4-HNE), was strong in the liver but was absent in the lung, suggesting that CCl4 did not directly induce oxidative injury in the lung. Pulmonary acceleration time (PAT) and the ratio of PAT/pulmonary ejection time (PET) measured by echocardiography were significantly decreased in cirrhotic mice. Increase in right ventricle (RV) weight/body weight as well as in the weight ratio of RV/(left ventricle + septum) further demonstrated the presence of pathological changes in the pulmonary circulation in these mice. Histological examination revealed that lungs of cirrhotic mice have excessive accumulation of perivascular collagen and thickening of the media of the pulmonary artery.
    Conclusion: Collectively, our data demonstrate that chronic CCl4 treatment induces pathological changes in pulmonary circulation in cirrhotic mice. We propose that this murine cirrhotic model provides an exceptional tool for future studies of the molecular mechanisms mediating pulmonary vascular diseases associated with cirrhosis and for evaluation of novel therapeutic interventions.
    MeSH term(s) Animals ; Carbon Tetrachloride ; Collagen/metabolism ; Disease Models, Animal ; Fatty Acids, Unsaturated/metabolism ; Hydroxy Acids/metabolism ; Hypertension, Pulmonary/chemically induced ; Hypertension, Pulmonary/pathology ; Hypertension, Pulmonary/physiopathology ; Liver/pathology ; Liver Cirrhosis/chemically induced ; Liver Cirrhosis/pathology ; Liver Cirrhosis/physiopathology ; Lung/metabolism ; Lung/pathology ; Lung/physiopathology ; Male ; Mice, Inbred C57BL ; Oxidative Stress
    Chemical Substances 4-hydroxynonenoic acid ; Fatty Acids, Unsaturated ; Hydroxy Acids ; Collagen (9007-34-5) ; Carbon Tetrachloride (CL2T97X0V0)
    Language English
    Publishing date 2014-04-24
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ISSN 1932-6203
    ISSN (online) 1932-6203
    DOI 10.1371/journal.pone.0096043
    Database MEDical Literature Analysis and Retrieval System OnLINE

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