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LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Overview

In one in five people with NAFLD, the functioning liver cells, the hepatocytes, are replaced by connective tissue. Eventually this fibrosis becomes irreversible. In this state the liver is like a ‘scar that never heals’. Through it, the liver loses many of its vital functions.
LiSyM-Pillar II wants to know more about which factors promote fibrosis and the conditions under which fibrosis becomes irreversible How can fibrosis be diagnosed as early as possible? Researchers in the pillar are also developing anti-fibrotic drugs, but these are not yet available.

SEEK ID: https://seek.lisym.org/projects/4

Public web page: http://www.lisym.org/our-work/pillar-research

Organisms: Mus musculus, Rattus rattus, Rattus norvegicus, Homo sapiens

FAIRDOM PALs: Janine Koehncke, Annika Schneider, Daniel Lill, Seddik Hammad, Matthias Reichert

Project start date: 1st Jan 2016

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Claire Barbieux

Projects: LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM network

Institutions: Deutsches Krebsforschungszentrum

Johannes Bausch : inactive since 2018-05-16

Projects: LiSyM Core Infrastructure and Management (LiSyM-PD), LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI), LiSyM Pillar IV: Liver Function Diagnostics (LiSyM-LiFuDi), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM network, LiSyM Scientific Leadership Team (LiSyM-LT)

Institutions: University of Freiburg - Institute of Physics, LiSyM programme directorate

https://orcid.org/0000-0002-1003-1682
Marie-Luise Berres

Projects: LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM network

Institutions: RWTH Aachen University Hospital - Department of Internal Medicine III

Johannes Bode

Projects: LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM network, LiSyM-Krebs Partnering

Institutions: Universitätsklinikum Düsseldorf - Klinik für Gastroenterologie, Hepatologie und Infektiologie

Lorenza D'Alessandro

Projects: LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM network, LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Institutions: Deutsches Krebsforschungszentrum

LiSyM Pillar II: Chronic Liver Disease Progression
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
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LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Pillar II dooley

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CCl4 Treatment in mice
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
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Person responsible: Seddik Hammad

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Metabolic CCl4
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Submitter: Seddik Hammad

Assay type: Proteomics

Technology type: FACS

Snapshots: No snapshots

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Robustness and applicability of transcription factor and pathway analysis tools on single-cell RNA-seq data
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

GitHub repository containing the analysis code

Creator: Christian Holland

Submitter: Christian Holland

External Link
Transfer of regulatory knowledge from human to mouse for functional genomics analysis
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

GitHub repository that contains all analyses scripts to reproduce the results reported in "Transfer of regulatory knowledge from human to mouse for functional genomics analysis"

Creator: Christian Holland

Submitter: Christian Holland

Movies for quantification
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
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Creator: Seddik Hammad

Submitter: Seddik Hammad

TextBookData
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
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Creators: None

Submitter: Seddik Hammad

F4-80
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
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Creators: None

Submitter: Seddik Hammad

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SOP RNA Isolation from healthy and fatty liver
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF)
No description specified

Creator: Sonja Kleeschulte

Submitter: Sonja Kleeschulte

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SOP FACS analysis of Macrophage population in healthy and fatty liver
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF)

Non-parenchymal liver cells are isolated and staining for FACS analysis

Creator: Sonja Kleeschulte

Submitter: Sonja Kleeschulte

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SOP Immunhistochemistry Mac2 staining
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF)

Macrophage staining in paraffin-embedded tissue

Creator: Sonja Kleeschulte

Submitter: Sonja Kleeschulte

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Robustness and applicability of transcription factor and pathway analysis tools on single-cell RNA-seq data
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM network

Abstract (Expand)

Background Many functional analysis tools have been developed to extract functional and mechanistic insight from bulk transcriptome data. With the advent of single-cell RNA sequencing (scRNA-seq), it … is in principle possible to do such an analysis for single cells. However, scRNA-seq data has characteristics such as drop-out events and low library sizes. It is thus not clear if functional TF and pathway analysis tools established for bulk sequencing can be applied to scRNA-seq in a meaningful way. Results To address this question, we perform benchmark studies on simulated and real scRNA-seq data. We include the bulk-RNA tools PROGENy, GO enrichment, and DoRothEA that estimate pathway and transcription factor (TF) activities, respectively, and compare them against the tools SCENIC/AUCell and metaVIPER, designed for scRNA-seq. For the in silico study, we simulate single cells from TF/pathway perturbation bulk RNA-seq experiments. We complement the simulated data with real scRNA-seq data upon CRISPR-mediated knock-out. Our benchmarks on simulated and real data reveal comparable performance to the original bulk data. Additionally, we show that the TF and pathway activities preserve cell type-specific variability by analyzing a mixture sample sequenced with 13 scRNA-seq protocols. We also provide the benchmark data for further use by the community. Conclusions Our analyses suggest that bulk-based functional analysis tools that use manually curated footprint gene sets can be applied to scRNA-seq data, partially outperforming dedicated single-cell tools. Furthermore, we find that the performance of functional analysis tools is more sensitive to the gene sets than to the statistic used.

Authors: Christian H. Holland, Jovan Tanevski, Javier Perales-Patón, Jan Gleixner, Manu P. Kumar, Elisabetta Mereu, Brian A. Joughin, Oliver Stegle, Douglas A. Lauffenburger, Holger Heyn, Bence Szalai, Julio Saez-Rodriguez

Date Published: 1st Dec 2020

Publication Type: Not specified

Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction.
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF)

Abstract (Expand)

Tightly interlinked feedback regulators control the dynamics of intracellular responses elicited by the activation of signal transduction pathways. Interferon alpha (IFNalpha) orchestrates antiviral … responses in hepatocytes, yet mechanisms that define pathway sensitization in response to prestimulation with different IFNalpha doses remained unresolved. We establish, based on quantitative measurements obtained for the hepatoma cell line Huh7.5, an ordinary differential equation model for IFNalpha signal transduction that comprises the feedback regulators STAT1, STAT2, IRF9, USP18, SOCS1, SOCS3, and IRF2. The model-based analysis shows that, mediated by the signaling proteins STAT2 and IRF9, prestimulation with a low IFNalpha dose hypersensitizes the pathway. In contrast, prestimulation with a high dose of IFNalpha leads to a dose-dependent desensitization, mediated by the negative regulators USP18 and SOCS1 that act at the receptor. The analysis of basal protein abundance in primary human hepatocytes reveals high heterogeneity in patient-specific amounts of STAT1, STAT2, IRF9, and USP18. The mathematical modeling approach shows that the basal amount of USP18 determines patient-specific pathway desensitization, while the abundance of STAT2 predicts the patient-specific IFNalpha signal response.

Authors: F. Kok, M. Rosenblatt, M. Teusel, T. Nizharadze, V. Goncalves Magalhaes, C. Dachert, T. Maiwald, A. Vlasov, M. Wasch, S. Tyufekchieva, K. Hoffmann, G. Damm, D. Seehofer, T. Boettler, M. Binder, J. Timmer, M. Schilling, U. Klingmuller

Date Published: 23rd Jul 2020

Publication Type: Journal

Lipid-encapsulated siRNA for hepatocyte-directed treatment of advanced liver disease
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM Pillar III: Regeneration and Repair in Acute-on-Chronic Liver Failure (LiSyM-ACLF), LiSyM network

Abstract (Expand)

Lipid-based RNA nanocarriers have been recently accepted as a novel therapeutic option in humans, thus increasing the therapeutic options for patients. Tailored nanomedicines will enable to treat chronic … liver disease (CLD) and end-stage liver cancer, disorders with high mortality and few treatment options. Here, we investigated the curative potential of gene therapy of a key molecule in CLD, the c-Jun N-terminal kinase-2 (Jnk2). Delivery to hepatocytes was achieved using a lipid-based clinically employable siRNA formulation that includes a cationic aminolipid to knockdown Jnk2 (named siJnk2). After assessing the therapeutic potential of siJnk2 treatment, non-invasive imaging demonstrated reduced apoptotic cell death and improved hepatocarcinogenesis was evidenced by improved liver parenchyma as well as ameliorated markers of hepatic damage, reduced fibrogenesis in 1-year-old mice. Strikingly, chronic siJnk2 treatment reduced premalignant nodules, indicative of tumor initiation. Furthermore, siJnk2 treatment led to a significant activation of the immune cell compartment. In conclusion, Jnk2 knockdown in hepatocytes ameliorated hepatitis, fibrogenesis, and initiation of hepatocellular carcinoma (HCC), and hence might be a suitable therapeutic option, to define novel molecular targets for precision medicine in CLD.

Authors: Marius Maximilian Woitok, Miguel Eugenio Zoubek, Dennis Doleschel, Matthias Bartneck, Mohamed Ramadan Mohamed, Fabian Kießling, Wiltrud Lederle, Christian Trautwein, Francisco Javier Cubero

Date Published: 1st May 2020

Publication Type: Journal

TGF-β2 silencing to target biliary-derived liver diseases
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Abstract

Not specified

Authors: Anne Dropmann, Steven Dooley, Bedair Dewidar, Seddik Hammad, Tatjana Dediulia, Julia Werle, Vanessa Hartwig, Shahrouz Ghafoory, Stefan Woelfl, Hanna Korhonen, Michel Janicot, Katja Wosikowski, Timo Itzel, Andreas Teufel, Detlef Schuppan, Ana Stojanovic, Adelheid Cerwenka, Stefanie Nittka, Albrecht Piiper, Timo Gaiser, Naiara Beraza, Malgorzata Milkiewicz, Piotr Milkiewicz, John G Brain, David E J Jones, Thomas S Weiss, Ulrich M Zanger, Matthias Ebert, Nadja M Meindl-Beinker

Date Published: 28th Jan 2020

Publication Type: Not specified

TGF-beta in Hepatic Stellate Cell Activation and Liver Fibrogenesis-Updated 2019.
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

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

CYP2E1 recovery is associated with a pericentral fibrosis pattern after repeated CCl4 insults
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Creator: Seddik Hammad

Submitter: Seddik Hammad

Cellular and nuclear hepatocyte ploidy represent a repository in regenerating livers
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Creator: Seddik Hammad

Submitter: Seddik Hammad

Decreased ECM1 expression is consistent in HCC and correlates with overall survival
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Creator: Seddik Hammad

Submitter: Seddik Hammad

GPNMB as hepatocytic suppressor of steatosis and liver cancer
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

Creator: Seddik Hammad

Submitter: Seddik Hammad

Robustness and applicability of functional genomic tools on scRNA-seq data
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP), LiSyM network
No description specified

Creator: Christian Holland

Submitter: Christian Holland

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