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Published year: 201920
TGF-beta in Hepatic Stellate Cell Activation and Liver Fibrogenesis-Updated 2019.

Abstract (Expand)

Liver fibrosis is an advanced liver disease condition, which could progress to cirrhosis and hepatocellular carcinoma. To date, there is no direct approved antifibrotic therapy, and current treatment … is mainly the removal of the causative factor. Transforming growth factor (TGF)-beta is a master profibrogenic cytokine and a promising target to treat fibrosis. However, TGF-beta has broad biological functions and its inhibition induces non-desirable side effects, which override therapeutic benefits. Therefore, understanding the pleiotropic effects of TGF-beta and its upstream and downstream regulatory mechanisms will help to design better TGF-beta based therapeutics. Here, we summarize recent discoveries and milestones on the TGF-beta signaling pathway related to liver fibrosis and hepatic stellate cell (HSC) activation, emphasizing research of the last five years. This comprises impact of TGF-beta on liver fibrogenesis related biological processes, such as senescence, metabolism, reactive oxygen species generation, epigenetics, circadian rhythm, epithelial mesenchymal transition, and endothelial-mesenchymal transition. We also describe the influence of the microenvironment on the response of HSC to TGF-beta. Finally, we discuss new approaches to target the TGF-beta pathway, name current clinical trials, and explain promises and drawbacks that deserve to be adequately addressed.

Authors: B. Dewidar, C. Meyer, S. Dooley, A. N. Meindl-Beinker

Date Published: 11th Nov 2019

Publication Type: Not specified

Transfer of regulatory knowledge from human to mouse for functional genomics analysis

Abstract (Expand)

Transcriptome profiling followed by differential gene expression analysis often leads to lists of genes that are hard to analyze and interpret. Functional genomics tools are powerful approaches for … downstream analysis, as they summarize the large and noisy gene expression space into a smaller number of biological meaningful features. In particular, methods that estimate the activity of processes by mapping transcripts level to process members are popular. However, footprints of either a pathway or transcription factor (TF) on gene expression show superior performance over mapping-based gene sets. These footprints are largely developed for humans and their usability in the broadly-used model organism Mus musculus is uncertain. Evolutionary conservation of the gene regulatory system suggests that footprints of human pathways and TFs can functionally characterize mice data. In this paper we analyze this hypothesis. We perform a comprehensive benchmark study exploiting two state-of-the-art footprint methods, DoRothEA and an extended version of PROGENy. These methods infer TF and pathway activity, respectively. Our results show that both can recover mouse perturbations, confirming our hypothesis that footprints are conserved between mice and humans. Subsequently, we illustrate the usability of PROGENy and DoRothEA by recovering pathway/TF-disease associations from newly generated disease sets. Additionally, we provide pathway and TF activity scores for a large collection of human and mouse perturbation and disease experiments (2374). We believe that this resource, available for interactive exploration and download (https://saezlab.shinyapps.io/footprint_scores/), can have broad applications including the study of diseases and therapeutics.

Authors: Christian H. Holland, Bence Szalai, Julio Saez-Rodriguez

Date Published: 1st Sep 2019

Publication Type: Not specified

Assessment of Chemotherapy-Induced Organ Damage with Ga-68 Labeled Duramycin.

Abstract (Expand)

PURPOSE: Evaluation of [(68)Ga]NODAGA-duramycin as a positron emission tomography (PET) tracer of cell death for whole-body detection of chemotherapy-induced organ toxicity. PROCEDURES: Tracer specificity … of Ga-68 labeled NODAGA-duramycin was determined in vitro using competitive binding experiments. Organ uptake was analyzed in untreated and doxorubicin, busulfan, and cisplatin-treated mice 2 h after intravenous injection of [(68)Ga]NODAGA-duramycin. In vivo data were validated by immunohistology and blood parameters. RESULTS: In vitro experiments confirmed specific binding of [(68)Ga]NODAGA-duramycin. Organ toxicities were detected successfully using [(68)Ga]NODAGA-duramycin PET/X-ray computed tomography (CT) and confirmed by immunohistochemistry and blood parameter analysis. Organ toxicities in livers and kidneys showed similar trends in PET/CT and immunohistology. Busulfan and cisplatin-related organ toxicities in heart, liver, and lungs were detected earlier by PET/CT than by blood parameters and immunohistology. CONCLUSION: [(68)Ga]NODAGA-duramycin PET/CT was successfully applied to non-invasively detect chemotherapy-induced organ toxicity with high sensitivity in mice. It, therefore, represents a promising alternative to standard toxicological analyses with a high translational potential.

Authors: A. Rix, N. I. Drude, A. Mrugalla, F. Baskaya, K. Y. Pak, B. Gray, H. J. Kaiser, R. H. Tolba, E. Fiegle, W. Lederle, F. M. Mottaghy, F. Kiessling

Date Published: 8th Aug 2019

Publication Type: Not specified

Benchmark and integration of resources for the estimation of human transcription factor activities

Abstract (Expand)

The prediction of transcription factor (TF) activities from the gene expression of their targets (i.e., TF regulon) is becoming a widely used approach to characterize the functional status of transcriptional … regulatory circuits. Several strategies and data sets have been proposed to link the target genes likely regulated by a TF, each one providing a different level of evidence. The most established ones are (1) manually curated repositories, (2) interactions derived from ChIP-seq binding data, (3) in silico prediction of TF binding on gene promoters, and (4) reverse-engineered regulons from large gene expression data sets. However, it is not known how these different sources of regulons affect the TF activity estimations and, thereby, downstream analysis and interpretation. Here we compared the accuracy and biases of these strategies to define human TF regulons by means of their ability to predict changes in TF activities in three reference benchmark data sets. We assembled a collection of TF–target interactions for 1541 human TFs and evaluated how different molecular and regulatory properties of the TFs, such as the DNA-binding domain, specificities, or mode of interaction with the chromatin, affect the predictions of TF activity. We assessed their coverage and found little overlap on the regulons derived from each strategy and better performance by literature-curated information followed by ChIP-seq data. We provide an integrated resource of all TF–target interactions derived through these strategies, with confidence scores, as a resource for enhanced prediction of TF activities.

Authors: Luz Garcia-Alonso, Christian H. Holland, Mahmoud M. Ibrahim, Denes Turei, Julio Saez-Rodriguez

Date Published: 1st Aug 2019

Publication Type: Not specified

Genetic Variants in the Promoter Region of the Macrophage Migration Inhibitory Factor are Associated with the Severity of Hepatitis C Virus-Induced Liver Fibrosis.

Abstract (Expand)

Two polymorphisms in the promoter region of macrophage migration inhibitory factor (MIF) - rs755622 and rs5844572 - exhibit prognostic relevance in inflammatory diseases. The aim of this study was to … investigate a correlation between these MIF promoter polymorphisms and the severity of hepatitis C virus (HCV)-induced liver fibrosis. Our analysis included two independent patient cohorts with HCV-induced liver fibrosis (504 and 443 patients, respectively). The genotype of the single nucleotide polymorphism (SNP) -173 G/C and the repeat number of the microsatellite polymorphism -794 CATT5-8 were determined in DNA samples and correlated with fibrosis severity. In the first cohort, homozygous carriers of the C allele in the rs755622 had lower fibrosis stages compared to heterozygous carriers or wild types (1.25 vs. 2.0 vs. 2.0; p = 0.03). Additionally, >/=7 microsatellite repeats were associated with lower fibrosis stages (<F2) (p = 0.04). Comparable tendencies were observed in the second independent cohort, where fibrosis was assessed using transient elastography. However, once cirrhosis had been established, the C/C genotype and higher microsatellite repeats correlated with impaired liver function and a higher prevalence of hepatocellular carcinoma. Our study demonstrates that specific MIF polymorphisms are associated with disease severity and complications of HCV-induced fibrosis in a stage- and context-dependent manner.

Authors: T. H. Wirtz, P. Fischer, C. Backhaus, I. Bergmann, E. F. Brandt, D. Heinrichs, M. T. Koenen, K. M. Schneider, T. Eggermann, I. Kurth, C. Stoppe, J. Bernhagen, T. Bruns, J. Fischer, T. Berg, C. Trautwein, M. L. Berres

Date Published: 31st Jul 2019

Publication Type: Journal

Cooperative and distinct functions of MK2 and MK3 in the regulation of the macrophage transcriptional response to lipopolysaccharide.

Abstract (Expand)

The p38(MAPK) downstream targets MAPKAP kinases (MK) 2 and 3 are critical for the regulation of the macrophage response to LPS. The extents to which these two kinases act cooperatively and distinctly … in regulating LPS-induced inflammatory cytokine expression are still unclear. To address this uncertainty, whole transcriptome analyses were performed using bone marrow-derived macrophages (BMDM) generated from MK2(-/-) or MK2/3(-/-) animals and their wild-type littermates. The results suggest that in BMDM, MK2 and MK3 not only cooperatively regulate the transcript expression of signaling intermediates, including IL-10, IL-19, CXCL2 and the IL-4 receptor (IL-4R)alpha subunit, they also exert distinct regulatory effects on the expression of specific transcripts. Based on the differential regulation of gene expression by MK2 and MK3, at least six regulatory patterns were identified. Importantly, we confirmed our previous finding, which showed that in the absence of MK2, MK3 negatively regulates IFN-beta. Moreover, this genome-wide analysis identified the regulation of Cr1A, NOD1 and Serpina3f as similar to that of IFN-beta. In the absence of MK2, MK3 also delayed the nuclear translocation of NFkappaB by delaying the ubiquitination and subsequent degradation of IkappaBbeta, reflecting the substantial plasticity of the response of BMDM to LPS.

Authors: C. Ehlting, J. Rex, U. Albrecht, R. Deenen, C. Tiedje, K. Kohrer, O. Sawodny, M. Gaestel, D. Haussinger, J. G. Bode

Date Published: 30th Jul 2019

Publication Type: Not specified

ECM1 Prevents Activation of Transforming Growth Factor beta, Hepatic Stellate Cells, and Fibrogenesis in Mice.

Abstract (Expand)

BACKGROUND & AIMS: Activation of transforming growth factor beta (TGFB) promotes liver fibrosis by activating hepatic stellate cells (HSCs), but the mechanism of TGFB activation are not clear. We … investigated the role of extracellular matrix protein 1 (ECM1), which interacts with extracellular and structural proteins, in TGFB activation in livers of mice. METHODS: We performed studies with e C57BL/6J mice (controls), ECM1-knockout (ECM1-KO) mice, and mice with hepatocyte-specific knockout of EMC1 (ECM1Deltahep). ECM1 or soluble TGFB receptor 2 (TGFBR2) were expressed in livers of mice following injection of an adeno-associated virus vector. Liver fibrosis was induced by carbon tetrachloride (CCl4) administration. Livers were collected from mice and analyzed by histology, immunohistochemistry, in situ hybridization, and immunofluorescence analyses. Hepatocytes and HSCs were isolated from livers of mice and incubated with ECM1; production of cytokines and activation of reporter genes were quantified. Liver tissues from patients with viral or alcohol-induced hepatitis (with different stages of fibrosis) and individuals with healthy liver were analyzed by immunohistochemistry and in situ hybridization. RESULTS: ECM1-KO mice spontaneously developed liver fibrosis and died by 2 months of age without significant hepatocyte damage or inflammation. In liver tissues of mice, we found that ECM1 stabilized extracellular matrix-deposited TGFB in its inactive form by interacting with alphav integrins to prevent activation of HSCs. In liver tissues from patients and in mice with CCl4-induced liver fibrosis, we found an inverse correlation between level of ECM1 and severity of fibrosis. CCl4-induced liver fibrosis was accelerated in ECM1Deltahep mice compared with control mice. Hepatocytes produced the highest levels of ECM1 in livers of mice. Ectopic expression of ECM1 or soluble TGFBR2 in liver prevented fibrogenesis in ECM1-KO mice and prolonged their survival. Ectopic expression of ECM1 in liver also reduced the severity of CCl4-induced fibrosis in mice. CONCLUSIONS: ECM1, produced by hepatocytes, inhibits activation of TGFB and its activation of HSCs to prevent fibrogenesis in mouse liver. Strategies to increase levels of ECM1 in liver might be developed for treatment of fibrosis.

Authors: W. Fan, T. Liu, W. Chen, S. Hammad, T. Longerich, Y. Fu, N. Li, Y. He, C. Liu, Y. Zhang, Q. Lian, X. Zhao, C. Yan, L. Li, C. Yi, Z. Ling, L. Ma, X. Zhao, H. Xu, P. Wang, M. Cong, H. You, Z. Liu, Y. Wang, J. Chen, D. Li, L. Hui, S. Dooley, J. Hou, J. Jia, B. Sun

Date Published: 27th Jul 2019

Publication Type: Not specified

Adenovirusmediated overexpression of bone morphogenetic protein9 promotes methionine choline deficiencyinduced nonalcoholic steatohepatitis in nonobese mice.

Abstract (Expand)

Liver inflammation and macrophage infiltration are critical steps in the progression of nonalcoholic fatty liver to the development of nonalcoholic steatohepatitis. Bone morphogenetic protein9 is a … cytokine involved in the regulation of chemokines and lipogenesis. However, the function of bone morphogenetic protein9 in nonalcoholic steatohepatitis is still unknown. The present study hypothesized that bone morphogenetic protein9 may contribute to steatohepatitis in mice fed a methionine choline deficiency diet (MCD). C57BL/6 mice overexpressing bone morphogenetic protein9 and control mice were fed the MCD diet for 4 weeks. Liver tissue and serum samples were obtained for subsequent measurements. Bone morphogenetic protein9 overexpression exacerbated steatohepatitis in mice on the MCD diet, as indicated by liver histopathology, increased serum alanine aminotransferase activity, aspartate transaminase activity, hepatic inflammatory gene expression and M1 macrophage recruitment. Although bone morphogenetic protein9 overexpression did not affect the expression of profibrogenic genes, including Collagen I (alpha)1 or matrix metalloproteinase (MMP) 9, it did upregulate the expression of transforming growth factorbeta and plasminogen activator inhibitor 1, and downregulated the expression of MMP2. The above results indicate that bone morphogenetic protein9 exerts a proinflammatory role in MCD dietinduced nonalcoholic steatohepatitis.

Authors: Q. Li, B. Liu, K. Breitkopf-Heinlein, H. Weng, Q. Jiang, P. Dong, S. Dooley, K. Xu, H. Ding

Date Published: 20th Jul 2019

Publication Type: Not specified

Glial cell line-derived neurotrophic factor (GDNF) mediates hepatic stellate cell activation via ALK5/Smad signalling.

Abstract (Expand)

OBJECTIVE: Although glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-beta superfamily, its function in liver fibrosis has rarely been studied. Here, we … investigated the role of GDNF in hepatic stellate cell (HSC) activation and liver fibrosis in humans and mice. DESIGN: GDNF expression was examined in liver biopsies and sera from patients with liver fibrosis. The functional role of GDNF in liver fibrosis was examined in mice with adenoviral delivery of the GDNF gene, GDNF sgRNA CRISPR/Cas9 and the administration of GDNF-blocking antibodies. GDNF was examined on HSC activation using human and mouse primary HSCs. The binding of activin receptor-like kinase 5 (ALK5) to GDNF was determined using surface plasmon resonance (SPR), molecular docking, mutagenesis and co-immunoprecipitation. RESULTS: GDNF mRNA and protein levels are significantly upregulated in patients with stage F4 fibrosis. Serum GDNF content correlates positively with alpha-smooth muscle actin (alpha-SMA) and Col1A1 mRNA in human fibrotic livers. Mice with overexpressed GDNF display aggravated liver fibrosis, while mice with silenced GDNF expression or signalling inhibition by GDNF-blocking antibodies have reduced fibrosis and HSC activation. GDNF is confined mainly to HSCs and contributes to HSC activation through ALK5 at His(39) and Asp(76) and through downstream signalling via Smad2/3, but not through GDNF family receptor alpha-1 (GFRalpha1). GDNF, ALK5 and alpha-SMA colocalise in human and mouse HSCs, as demonstrated by confocal microscopy. CONCLUSIONS: GDNF promotes HSC activation and liver fibrosis through ALK5/Smad signalling. Inhibition of GDNF could be a novel therapeutic strategy to combat liver fibrosis.

Authors: L. Tao, W. Ma, L. Wu, M. Xu, Y. Yang, W. Zhang, W. Sha, H. Li, J. Xu, R. Feng, D. Xue, J. Zhang, S. Dooley, E. Seki, P. Liu, C. Liu

Date Published: 6th Jun 2019

Publication Type: Not specified

Local Riemannian geometry of model manifolds and its implications for practical parameter identifiability

Abstract (Expand)

When non-linear models are fitted to experimental data, parameter estimates can be poorly constrained albeit being identifiable in principle. This means that along certain paths in parameter space, the … log-likelihood does not exceed a given statistical threshold but remains bounded. This situation, denoted as practical non-identifiability, can be detected by Monte Carlo sampling or by systematic scanning using the profile likelihood method. In contrast, any method based on a Taylor expansion of the log-likelihood around the optimum, e.g., parameter uncertainty estimation by the Fisher Information Matrix, reveals no information about the boundedness at all. In this work, we present a geometric approach, approximating the original log-likelihood by geodesic coordinates of the model manifold. The Christoffel Symbols in the geodesic equation are fixed to those obtained from second order model sensitivities at the optimum. Based on three exemplary non-linear models we show that the information about the log-likelihood bounds and flat parameter directions can already be contained in this local information. Whereas the unbounded case represented by the Fisher Information Matrix is embedded in the geometric framework as vanishing Christoffel Symbols, non-vanishing constant Christoffel Symbols prove to define prototype non-linear models featuring boundedness and flat parameter directions of the log-likelihood. Finally, we investigate if those models could allow to approximate and replace computationally expensive objective functions originating from non-linear models by a surrogate objective function in parameter estimation problems.

Authors: Daniel Lill, Jens Timmer, Daniel Kaschek

Date Published: 3rd Jun 2019

Publication Type: Not specified

Mapping connections in signaling networks with ambiguous modularity.

Abstract (Expand)

Modular Response Analysis (MRA) is a suite of methods that under certain assumptions permits the precise reconstruction of both the directions and strengths of connections between network modules from … network responses to perturbations. Standard MRA assumes that modules are insulated, thereby neglecting the existence of inter-modular protein complexes. Such complexes sequester proteins from different modules and propagate perturbations to the protein abundance of a downstream module retroactively to an upstream module. MRA-based network reconstruction detects retroactive, sequestration-induced connections when an enzyme from one module is substantially sequestered by its substrate that belongs to a different module. Moreover, inferred networks may surprisingly depend on the choice of protein abundances that are experimentally perturbed, and also some inferred connections might be false. Here, we extend MRA by introducing a combined computational and experimental approach, which allows for a computational restoration of modular insulation, unmistakable network reconstruction and discrimination between solely regulatory and sequestration-induced connections for a range of signaling pathways. Although not universal, our approach extends MRA methods to signaling networks with retroactive interactions between modules arising from enzyme sequestration effects.

Authors: D. Lill, O. S. Rukhlenko, A. J. Mc Elwee, E. Kashdan, J. Timmer, B. N. Kholodenko

Date Published: 1st Jun 2019

Publication Type: Not specified

Second exposure to acetaminophen overdose is associated with liver fibrosis in mice

Abstract (Expand)

Repeated administration of hepatotoxicants is usually accompanied by liver fibrosis. However, the difference in response as a result of repeated exposures of acetaminophen (APAP) compared to a single … dose is not well-studied. Therefore, in the current study, the liver response after a second dose of APAP was investigated. Adult fasted Balb/C mice were exposed to two toxic doses of 300 mg/kg APAP, which were administered 72 h apart from each other. Subsequently, blood and liver from the treated mice were collected 24 h and 72 h after both APAP admin-istrations. Liver transaminase, i.e. alanine amino transferase (ALT) and aspartate amino transferase (AST) levels revealed that the fulminant liver damage was reduced after the second APAP administration compared to that observed at the same time point after the first treatment. These results correlated with the necrotic areas as indicated by histological analyses. Surprisingly, Picro Sirius Red (PSR) staining showed that the accumulation of extracel-lular matrix after the second dose coincides with the upregulation of some fibrogenic signatures, e.g., alpha smooth muscle actin. Non-targeted liver tissue metabolic profiling indicates that most alterations occur 24 h after the first dose of APAP. However, the levels of most metabolites recover to basal values over time. This organ adaptation process is also confirmed by the upregulation of antioxidative systems like e.g. superoxide dismutase and catalase. From the results, it can be concluded that there is a different response of the liver to APAP toxic doses, if the liver has already been exposed to APAP. A necroinflammatory process followed by a liver regeneration was observed after the first APAP exposure. However, fibrogenesis through the accumulation of extracellular matrix is observed after a second challenge. Therefore, further studies are required to mechanistically understand the so called “liver memory”

Author: Mohammad AlWahsh, Amnah Othman, Lama Hamadneh, Ahmad Telfah, Jörg Lambert, Suhair Hikmat, Amin Alassi, Fatma El Zahraa Mohamed, Roland Hergenröder, Tariq Al-Qirim, Steven Dooley, Seddik Hammad

Date Published: 6th Feb 2019

Publication Type: Not specified

Effect of alcohol on the interleukin 6-mediated inflammatory response in a new mouse model of acute-on-chronic liver injury

Abstract

Not specified

Authors: Ersin Karatayli, Rabea A. Hall, Susanne N. Weber, Steven Dooley, Frank Lammert

Date Published: 1st Feb 2019

Publication Type: Not specified

ECM1 is a gatekeeper that restrains TGF-β activation to maintain liver homeostasis and prevent fibrogenesis

Abstract

Not specified

Authors: S Dooley, W Fan, S Hammad, K Gould, T Longerich, T Liu, W Chen, C Liu, J Hou, J Jia, B Sun

Date Published: 2019

Publication Type: Not specified

Simultaneous isolation of parenchymal and non-parenchymal cells from healthy and diseased mice liver

Abstract

Not specified

Authors: B Dewidar, A Dropmann, K Gould, V Hartwig, C Dormann, S Dooley, S Hammad

Date Published: 2019

Publication Type: Not specified

Jagged-1 upregulation in stressed hepatocytes is crucial for liver regeneration

Abstract

Not specified

Authors: B Dewidar, S Hammad, MP Ebert, JG Hengstler, S Dooley

Date Published: 2019

Publication Type: Not specified

Cellular and nuclear hepatocyte ploidy represent a repository in regenerating livers

Abstract

Not specified

Authors: S Hammad, U Dahmen, A Othman, I Recklinghausen, JG Hengstler, U Klingmüller, S Dooley

Date Published: 2019

Publication Type: Not specified

Liver cell type specific discrimination of TGF-beta signaling and outcome in vitro and in vivo

Abstract

Not specified

Authors: M Han, ZC Nwosu, MP Ebert, S Hammad, S Dooley, C Meyer

Date Published: 2019

Publication Type: Not specified

CYP2E1 recovery is associated with a pericentral fibrosis pattern after repeated CCl4 insults

Abstract

Not specified

Authors: S Hammad, J Zhao, Y Yin, A Zaza, D Drasdo, JG Hengstler, S Dooley

Date Published: 2019

Publication Type: Not specified

ECM1 stabilizes matrix deposited latent TGF-β to maintain liver homeostasis and prevent fibrogenesis

Abstract

Not specified

Authors: S Hammad, W Fan, T Liu, W Chen, K Gould, T Longerich, I Haußer-Siller, J Hou, J Jia, B Sun, S Dooely

Date Published: 2019

Publication Type: Not specified

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