U Haas

University Hospital RWTH Aachen, Aachen, North Rhine-Westphalia, Germany

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Publications (36)159.52 Total impact

  • Journal of Hepatology 04/2015; 62:S473. DOI:10.1016/S0168-8278(15)30637-1 · 10.40 Impact Factor
  • Journal of Hepatology 04/2015; 62:S207. DOI:10.1016/S0168-8278(15)30044-1 · 10.40 Impact Factor
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    ABSTRACT: Platelet-derived growth factor-D (PDGF-D) is one member of PDGF growth factors and known to signal by binding to and activating its cognate receptor type β (PDGFR-β). Beside PDGF-B, PDGF-D is a potent growth factor for stellate cell growth and proliferation and therefore potentiates the extra cellular matrix deposition in liver fibrogenesis. We aimed to explore the signalling and molecular mechanisms of PDGF-D in liver fibrogenesis using the primary liver portal myofibroblasts and hepatic stellate cells. Unexpectedly we found PDGF-D to bind to PDGFR-α, thus inducing receptor endocytosis and decreasing the amount of PDGFR-α significantly. PDGF-D activates PDGFR-α specific tyrosine 754 and -1018 phosphorylation and CrkII, the adaptor protein that specifically recruits into activated PDGFR-α. As a novel finding we could also demonstrate that recombinant PDGFR-α-Fc chimera homodimer is able to bind PDGF-D and thus prevent PDGF-D signalling. PDGF-D does induce individual PDGFR-β specific tyrosine phosphorylation similar to the PDGF-B. Additionally, PDGF-D enhances extracellular matrix accumulation comparable to the PDGF-B isoform. PDGF-D signalling in pMF and HSC is identical to that of PDGF-B by binding to both PDGFR-α and -β. Copyright © 2015. Published by Elsevier Inc.
    Cellular Signalling 03/2015; 27(7). DOI:10.1016/j.cellsig.2015.03.012 · 4.47 Impact Factor
  • Zeitschrift für Gastroenterologie 01/2015; 53(01). DOI:10.1055/s-0034-1397163 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 01/2015; 53(01). DOI:10.1055/s-0034-1397081 · 1.67 Impact Factor
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    ABSTRACT: Platelet-derived growth factor-D (PDGF-D) is a more recent recognized growth factor involved in the regulation of several cellular processes, including cell proliferation, transformation, invasion, and angiogenesis by binding to and activating its cognate receptor PDGFR-β. After bile duct ligation or in the carbon tetrachloride-induced hepatic fibrosis model, PDGF-D showed upregulation comparable to PDGF-B. Moreover, adenoviral PDGF-D gene transfer induced hepatic stellate cell proliferation and liver fibrosis. We here investigated the molecular mechanism of PDGF-D involvement in liver fibrogenesis. Therefore, the GRX mouse cell line was stimulated with PDGF-D and evaluated for fibrotic markers and PDGF-D signaling pathways in comparison to the other PDGF isoforms. We found that PDGF-D failed to enhance Col I and α-smooth muscle actin (α-SMA) production but has capacity to upregulate expression of the tissue inhibitor of metalloprotease 1 (TIMP-1) resulting in attenuation of MMP-2 and MMP-9 gelatinase activity as indicated by gelatinase zymography. This phenomenon was restored through application of a PDGF-D neutralizing antibody. Unexpectedly, PDGF-D incubation decreased both PDGFR-α and -β in mRNA and protein levels, and PDGF-D phosphorylated typrosines specific for PDGFR-α and -β. We conclude that PDGF-D intensifies fibrogenesis by interfering with the fibrolytic activity of the TIMP-1/MMP system and that PDGF-D signaling is mediated through both PDGF-α and -β receptors. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Biochemical and Biophysical Research Communications 01/2015; 457(3). DOI:10.1016/j.bbrc.2014.12.106 · 2.28 Impact Factor
  • Journal of Hepatology 04/2014; 60(1):S267. DOI:10.1016/S0168-8278(14)60755-8 · 10.40 Impact Factor
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    ABSTRACT: The liver has a strong regenerative capacity. Following injury, quiescent hepatocytes can re-enter the mitotic cell cycle to restore tissue homeostasis. This G0 /G1 -S cell cycle transition of primed hepatocytes is regulated by complexes of Cyclin-dependent kinase 2 (Cdk2) with E-type cyclins (CcnE1 or CcnE2). However, single genetic ablation of either E-cyclin or Cdk2 does not affect overall liver regeneration. Here, we systematically investigated the contribution of CcnE1, CcnE2 and Cdk2 for liver regeneration after partial hepatectomy (PH) by generating corresponding double and triple knockout mouse mutants. We demonstrate that conditional deletion of Cdk2 alone in hepatocytes resulted in accelerated induction of CcnE1 but otherwise normal initiation of S-phase in vivo and in vitro. Excessive CcnE1 did not contribute to a non-canonical kinase activity, but was located at chromatin together with components of the pre-replication complex such as the Minichromosome Maintenance (MCM) helicase. Concomitant ablation of Cdk2 and CcnE1 in hepatocytes caused a defect in pre-replication complex formation and further led to dramatically impaired S-phase progression via down-regulation of cyclin A2 and cell death in vitro and substantially reduced hepatocyte proliferation and liver regeneration after PH in vivo. Similarly, combined loss of CcnE1 and CcnE2 but also the Cdk2/CcnE1/CcnE2 triple knockout in liver significantly inhibited S-phase initiation and liver mass reconstitution after PH, while concomitant ablation of CcnE2 and Cdk2 had no effect. Conclusion: In absence of Cdk2, CcnE1 performs crucial kinase-independent functions in hepatocytes which are capable of driving MCM loading on chromatin, Cyclin A2 expression and S-phase progression. Thus, combined inactivation of Cdk2 and CcnE1 is the minimal requirement for blocking the S-phase machinery in vivo. (HEPATOLOGY 2013.).
    Hepatology 02/2014; 59(2). DOI:10.1002/hep.26584 · 11.19 Impact Factor
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    ABSTRACT: Cysteine-rich protein 61 (CCN1/CYR61) is a CCN family matricellular protein comprising six secreted CCN proteins in mammals. CCN1/CYR61 expression is associated with inflammation and injury repair. Recent studies show that CCN1/CYR61 limits fibrosis in models of cutaneous wound healing by inducing cellular senescence in myofibroblasts of the granulation tissue which thereby transforms into an extracellular matrix-degrading phenotype. We here investigate CCN1/CYR61 expression in primary profibrogenic liver cells (i.e., hepatic stellate cells and periportal myofibroblasts) and found an increase of CCN1/CYR61 expression during early activation of hepatic stellate cells that declines in fully transdifferentiated myofibroblasts. By contrast, CCN1/CYR61 levels found in primary parenchymal liver cells (i.e., hepatocytes) were relative low compared to the levels exhibited in hepatic stellate cells and portal myofibroblasts. In models of ongoing liver fibrogenesis, elevated levels of CCN1/CYR61 were particularly noticed during early periods of insult, while expression declined during prolonged phases of fibrogenesis. We generated an adenovirus type 5 encoding CCN1/CYR61 (i.e., Ad5-CMV-CCN1/CYR61) and overexpressed CCN1/CYR61 in primary portal myofibroblasts. Interestingly, overexpressed CCN1/CYR61 significantly inhibited production of collagen type I at both mRNA and protein levels as evidenced by quantitative real time PCR, Western blot and immunocytochemistry. CCN1/CYR61 further induces production of reactive oxygen species (ROS) leading to dose dependent cellular senescence and apoptosis. Additionally, we demonstrate that CCN1/CYR61 attenuate TGF-β signalling by scavenging TGF-β thereby mitigating in vivo liver fibrogenesis in a bile duct ligation model. In line with dermal fibrosis and scar formation, CCN1/CYR61 is involved in liver injury repair and tissue remodeling. CCN1/CYR61 gene transfer into extracellular matrix-producing liver cells is therefore potentially beneficial in liver fibrotic therapy.
    Biochimica et Biophysica Acta 01/2014; 1843(5). DOI:10.1016/j.bbamcr.2014.01.023 · 4.66 Impact Factor
  • Zeitschrift für Gastroenterologie 01/2014; 52(01). DOI:10.1055/s-0033-1360842 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 01/2014; 52(01). DOI:10.1055/s-0033-1360956 · 1.67 Impact Factor
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    ABSTRACT: Cysteine-rich protein 61 (CCN1/CYR61) is a CCN family matricellular protein comprising six secreted CCN proteins in mammals. CCN1/CYR61 expression is associated with inflammation and injury repair. Recent studies show that CCN1/CYR61 limits fibrosis in models of cutaneous wound healing by inducing cellular senescence in myofibroblasts of the granulation tissue which thereby transforms into an extracellular matrix-degrading phenotype. We here investigate CCN1/CYR61 expression in primary profibrogenic liver cells (i.e., hepatic stellate cells and periportal myofibroblasts) and found an increase of CCN1/CYR61 expression during early activation of hepatic stellate cells that declines in fully transdifferentiated myofibroblasts. By contrast, CCN1/CYR61 levels found in primary parenchymal liver cells (i.e., hepatocytes) were relative low compared to the levels exhibited in hepatic stellate cells and portal myofibroblasts. In models of ongoing liver fibrogenesis, elevated levels of CCN1/CYR61 were particularly noticed during early periods of insult, while expression declined during prolonged phases of fibrogenesis. We generated an adenovirus type 5 encoding CCN1/CYR61 (i.e., Ad5-CMV-CCN1/CYR61) and overexpressed CCN1/CYR61 in primary portal myofibroblasts. Interestingly, overexpressed CCN1/CYR61 significantly inhibited production of collagen type I at both mRNA and protein levels as evidenced by quantitative real time PCR, Western blot and immunocytochemistry. CCN1/CYR61 further induces production of reactive oxygen species (ROS) leading to dose dependent cellular senescence and apoptosis. Additionally, we demonstrate that CCN1/CYR61 attenuate TGF-β signalling by scavenging TGF-β thereby mitigating in vivo liver fibrogenesis in a bile duct ligation model. Conclusion In line with dermal fibrosis and scar formation, CCN1/CYR61 is involved in liver injury repair and tissue remodeling. CCN1/CYR61 gene transfer into extracellular matrix-producing liver cells is therefore potentially beneficial in liver fibrotic therapy.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 01/2014; · 5.30 Impact Factor
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    ABSTRACT: Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral and alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury, as well as cancer. Deletion of NF-κB essential modulator in hepatocytes (IKKγ/Nemo) causes spontaneous progression of TNF-mediated chronic hepatitis to hepatocellular carcinoma (HCC). Thus, we analyzed the role of death receptors including TNFR1 and TRAIL in the regulation of cell death and the progression of liver injury in IKKγ/Nemo-deleted livers. We crossed hepatocyte-specific IKKγ/Nemo knockout mice (Nemo(Δhepa)) with constitutive TNFR1(-/-) and TRAIL(-/-) mice. Deletion of TNFR1, but not TRAIL, decreased apoptotic cell death, compensatory proliferation, liver fibrogenesis, infiltration of immune cells as well as pro-inflammatory cytokines, and indicators of tumor growth during the progression of chronic liver injury. These events were associated with diminished JNK activation. In contrast, deletion of TNFR1 in bone-marrow-derived cells promoted chronic liver injury. Our data demonstrate that TNF- and not TRAIL signaling determines the progression of IKKγ/Nemo-dependent chronic hepatitis. Additionally, we show that TNFR1 in hepatocytes and immune cells have different roles in chronic liver injury-a finding that has direct implications for treating chronic liver disease.Cell Death and Differentiation advance online publication, 9 August 2013; doi:10.1038/cdd.2013.112.
    Cell death and differentiation 08/2013; 20(11). DOI:10.1038/cdd.2013.112 · 8.39 Impact Factor
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    ABSTRACT: BACKGROUND: Liver fibrosis is a consequence of chronic liver injury and can further progress to hepatocellular carcinoma (HCC). Fibrogenesis involves activation of hepatic stellate cells (HSC) and proliferation of hepatocytes upon liver injury. HCC is frequently associated with overexpression of the proto-oncogene c-myc. However, the impact of c-myc for initiating pathological precursor stages such as liver fibrosis is poorly characterized. In the present study we thus investigated the impact of c-myc for liver fibrogenesis. METHODS: Expression of c-myc was measured in biopsies of patients with liver fibrosis of different etiologies by quantitative real-time PCR (qPCR). Primary HSC were isolated from mice with transgenic overexpression of c-myc in hepatocytes (alb-myc(tg)) and wildtype (WT) controls and investigated for markers of cell cycle progression and fibrosis by qPCR and immunofluorescence microscopy. Liver fibrosis in WT and alb-myc(tg) mice was induced by repetitive CCl4 treatment. RESULTS: We detected strong up-regulation of hepatic c-myc in patients with advanced liver fibrosis. In return, overexpression of c-myc in alb-myc(tg) mice resulted in increased liver collagen deposition and induction of α-smooth-muscle-actin indicating HSC activation. Primary HSC derived from alb-myc(tg) mice showed enhanced proliferation and accelerated transdifferentiation into myofibroblasts in vitro. Accordingly, fibrosis initiation in vivo after chronic CCl4 treatment was accelerated in alb-myc(tg) mice compared to controls. CONCLUSION: Overexpression of c-myc is a novel marker of liver fibrosis in man and mice. We conclude that chronic induction of c-myc especially in hepatocytes has the potential to prime resident HSC for activation, proliferation and myofibroblast differentiation.
    Biochimica et Biophysica Acta 06/2013; 1832(10). DOI:10.1016/j.bbadis.2013.06.001 · 4.66 Impact Factor
  • Journal of Hepatology 04/2013; 58:S60-S61. DOI:10.1016/S0168-8278(13)60140-3 · 10.40 Impact Factor
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    ABSTRACT: Lipocalin-2 is expressed under pernicious conditions such as intoxication, infection, inflammation and other forms of cellular stress. Experimental liver injury induces rapid and sustained LCN2 production by injured hepatocytes. However, the precise biological function of LCN2 in liver is still unknown. In this study, LCN2(-/-) mice were exposed to short term application of CCl(4), lipopolysaccharide and Concanavalin A, or subjected to bile duct ligation. Subsequent injuries were assessed by liver function analysis, qRT-PCR for chemokine and cytokine expression, liver tissue Western blot, histology and TUNEL assay. Serum LCN2 levels from patients suffering from liver disease were assessed and evaluated. Acute CCl(4) intoxication showed increased liver damage in LCN2(-/-) mice indicated by higher levels of aminotransferases, and increased expression of inflammatory cytokines and chemokines such as IL-1β, IL-6, TNF-α and MCP-1/CCL2, resulting in sustained activation of STAT1, STAT3 and JNK pathways. Hepatocytes of LCN2(-/-) mice showed lipid droplet accumulation and increased apoptosis. Hepatocyte apoptosis was confirmed in the Concanavalin A and lipopolysaccharide models. In chronic models (4 weeks bile duct ligation or 8 weeks CCl(4) application), LCN2(-/-) mice showed slightly increased fibrosis compared to controls. Interestingly, serum LCN2 levels in diseased human livers were significantly higher compared to controls, but no differences were observed between cirrhotic and non-cirrhotic patients. Up-regulation of LCN2 is a reliable indicator of liver damage and has significant hepato-protective effect in acute liver injury. LCN2 levels provide no correlation to the degree of liver fibrosis but show significant positive correlation to inflammation instead.
    Biochimica et Biophysica Acta 01/2013; 1832(5). DOI:10.1016/j.bbadis.2013.01.014 · 4.66 Impact Factor
  • Zeitschrift für Gastroenterologie 01/2013; 51(01). DOI:10.1055/s-0032-1331946 · 1.67 Impact Factor
  • Zeitschrift für Gastroenterologie 01/2013; 51(01). DOI:10.1055/s-0032-1331904 · 1.67 Impact Factor
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    ABSTRACT: During inflammation, the inflammasomes representing a group of multi-protein complexes trigger the biological maturation of pro-inflammatory cytokines such as interleukin-1beta and interleukin-18 by proteolytic activation of caspase-1 from its inactive proforms. The individual genes encoding components of the inflammasome machinery are regulated at transcriptional and post-transcriptional levels. Once activated, they drive a wide variety of cellular responses that are necessary to mediate host defense against microbial pathogens and to guarantee tissue homeostasis. In the present work, we have studied the expression of the different inflammasomes in various primary hepatic cell subpopulations, in models of acute inflammation and during experimental liver fibrogenesis. We demonstrate that NLRP-1, NLRP-3 and AIM2 are prominently expressed in Kupffer cells and liver sinusoidal endothelial cells, moderately expressed in periportal myofibroblasts and hepatic stellate cells, and virtually absent in primary cultured hepatocytes. We found that the challenge with the lipopolysaccharides results in a time- and concentration-dependent expression of the NOD-like receptor family members NLRP-1, NLRP-3 and NLRC4/NALP4 in cultured hepatic stellate cells and a strong transcriptional activation of NLRP-3 in hepatocytes. Moreover, we detect a diverse regulatory network of the different inflammasomes in the chosen experimental models of acute and chronic liver insult suggesting that the various inflammasomes might contribute simultaneously to the outcome of inflammatory and fibrotic liver insult, irrespectively of the underlying inflammatory stimulus.
    Journal of Inflammation 11/2012; 9(1):49. DOI:10.1186/1476-9255-9-49 · 2.22 Impact Factor
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    ABSTRACT: Liver fibrogenesis is associated with the transition of quiescent hepatocytes and hepatic stellate cells (HSCs) into the cell cycle. Exit from quiescence is controlled by E-type cyclins (cyclin E1 [CcnE1] and cyclin E2 [CcnE2]). Thus, the aim of the current study was to investigate the contribution of E-type cyclins for liver fibrosis in man and mice. Expression of CcnE1, but not of its homolog, CcnE2, was induced in fibrotic and cirrhotic livers from human patients with different etiologies and in murine wild-type (WT) livers after periodical administration of the profibrotic toxin, CCl(4). To further evaluate the potential function of E-type cyclins for liver fibrogenesis, we repetitively treated constitutive CcnE1(-/-) and CcnE2(-/-) knock-out mice with CCl(4) to induce liver fibrosis. Interestingly, CcnE1(-/-) mice were protected against CCl(4)-mediated liver fibrogenesis, as evidenced by reduced collagen type I α1 expression and the lack of septum formation. In contrast, CcnE2(-/-) mice showed accelerated fibrogenesis after CCl(4) treatment. We isolated primary HSCs from WT, CcnE1(-/-), and CcnE2(-/-) mice and analyzed their activation, proliferation, and survival in vitro. CcnE1 expression in WT HSCs was maximal when they started to proliferate, but decreased after the cells transdifferentiated into myofibroblasts. CcnE1(-/-) HSCs showed dramatically impaired survival, cell-cycle arrest, and strongly reduced expression of alpha smooth muscle actin, indicating deficient HSC activation. In contrast, CcnE2-deficient HSCs expressed an elevated level of CcnE1 and showed enhanced cell-cycle activity and proliferation, compared to WT cells. CONCLUSIONS: CcnE1 and CcnE2 have antagonistic roles in liver fibrosis. CcnE1 is indispensable for the activation, proliferation, and survival of HSCs and thus promotes the synthesis of extracellular matrix and liver fibrogenesis.
    Hepatology 09/2012; 56(3):1140-9. DOI:10.1002/hep.25736 · 11.19 Impact Factor