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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.

Programme: LiSyM: Liver Systems Medicine

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, LiSyM-Krebs

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)
No description specified

Person responsible: Seddik Hammad

Snapshots: No snapshots

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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)
No description specified

Creator: Seddik Hammad

Submitter: Seddik Hammad

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

Creators: None

Submitter: Seddik Hammad

F4-80
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)
No description specified

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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Unexpected Pro-Fibrotic Effect of MIF in Non-Alcoholic Steatohepatitis Is Linked to a Shift in NKT Cell Populations
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Abstract (Expand)

Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine with anti-fibrotic properties in toxic liver injury models and anti-steatotic functions in non-alcoholic fatty liver … disease (NAFLD) attributed to the CD74/AMPK signaling pathway. As NAFLD progression is associated with fibrosis, we studied MIF function during NAFLD-associated liver fibrogenesis in mice and men by molecular, histological and immunological methods in vitro and in vivo. After NASH diet feeding, hepatic Mif expression was strongly induced, an effect which was absent in Mif∆hep mice. In contrast to hepatotoxic fibrosis models, NASH diet-induced fibrogenesis was significantly abrogated in Mif−/− and Mif∆hep mice associated with a reduced accumulation of the pro-fibrotic type-I NKT cell subpopulation. In vitro, MIF skewed the differentiation of NKT cells towards the type-I subtype. In line with the murine results, expression of fibrosis markers strongly correlated with MIF, its receptors, and markers of NKT type-I cells in NASH patients. We conclude that MIF expression is induced during chronic metabolic injury in mice and men with hepatocytes representing the major source. In NAFLD progression, MIF contributes to liver fibrogenesis skewing NKT cell polarization toward a pro-fibrotic phenotype highlighting the complex, context-dependent role of MIF during chronic liver injury.

Authors: D. Heinrichs, E. F. Brandt, P. Fischer, Janine Koehncke, Theresa H. Wirtz, N. Guldiken, S. Djudjaj, P. Boor, D.Kroy, R. Weiskirchen, Richard Bucala, H.E. Wasmuth, P. Strnad, Christian Trautwein, J. Bernhagen, M. L. Berres

Date Published: 28th Jan 2021

Publication Type: Journal

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: Journal

Balance between macrophage migration inhibitory factor and sCD74 predicts outcome in patients with acute decompensation of cirrhosis
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Abstract

Not specified

Authors: Theresa H. Wirtz, Philipp A. Reuken, Christian Jansen, Petra Fischer, Irina Bergmann, Christina Backhaus, Christoph Emontzpohl, Johanna Reißing, Elisa F. Brandt, M. Teresa Koenen, Kai M. Schneider, Robert Schierwagen, Maximilian J. Brol, Johannes Chang, Henning W. Zimmermann, Nilay Köse-Vogel, Thomas Eggermann, Ingo Kurth, Christian Stoppe, Richard Bucala, Jürgen Bernhagen, Michael Praktiknjo, Andreas Stallmach, Christian Trautwein, Jonel Trebicka, Tony Bruns, Marie-Luise Berres

Date Published: 1st Dec 2020

Publication Type: Journal

Simulation of a detoxifying organ function: Focus on hemodynamics modeling and convection-reaction numerical simulation in microcirculatory networks.
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)

When modeling a detoxifying organ function, an important component is the impact of flow on the metabolism of a compound of interest carried by the blood. We here study the effects of red blood cells … (such as the Fahraeus-Lindqvist effect and plasma skimming) on blood flow in typical microcirculatory components such as tubes, bifurcations and entire networks, with particular emphasis on the liver as important representative of detoxifying organs. In one of the plasma skimming models, under certain conditions, oscillations between states are found and analyzed in a methodical study to identify their causes and influencing parameters. The flow solution obtained is then used to define the velocity at which a compound would be transported. A convection-reaction equation is studied to simulate the transport of a compound in blood and its uptake by the surrounding cells. Different types of signal sharpness have to be handled depending on the application to address different temporal compound concentration profiles. To permit executing the studied models numerically stable and accurate, we here extend existing transport schemes to handle converging bifurcations, and more generally multi-furcations. We study the accuracy of different numerical schemes as well as the effect of reactions and of the network itself on the bolus shape. Even though this study is guided by applications in liver micro-architecture, the proposed methodology is general and can readily be applied to other capillary network geometries, hence to other organs or to bioengineered network designs.

Authors: N. Boissier, D. Drasdo, I. E. Vignon-Clementel

Date Published: 29th Nov 2020

Publication Type: Journal

Orphan Nuclear Receptor ERRγ Is a Novel Transcriptional Regulator of IL-6 Mediated Hepatic BMP6 Gene Expression in Mice
LiSyM Pillar II: Chronic Liver Disease Progression (LiSyM-DP)

Abstract

Not specified

Authors: Kamalakannan Radhakrishnan, Yong-Hoon Kim, Yoon Seok Jung, Jina Kim, Don-Kyu Kim, Sung Jin Cho, In-Kyu Lee, Steven Dooley, Chul-Ho Lee, Hueng-Sik Choi

Date Published: 1st Oct 2020

Publication Type: Journal

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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