LiSyM Pillar I: Early Metabolic Injury (LiSyM-EMI)

Liver Systems Medicine : striving to develop non-invasive methods for diagnosing and treating NAFLD by combining mathematical modeling and biological research. LiSyM, is a multidisciplinary research network, in which molecular and cell biologists, clinical researchers, pharmacologists and experts in mathematical modeling examine the liver in its entirety. LiSyM research focuses on the metabolic liver disease non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis ...

We apply multiphoton imaging, 3D digital reconstructions and computational simulations to generate spatially-resolved geometrical and functional models of human liver tissue at different stages of non-alcoholic fatty liver disease (NAFLD).

To investigate the underlying molecular principles of metabolic and morphogenic zonation of the human liver lobule, we generated an integrated epigenetic map across three zones (pericentral, intermediate and periportal) by methylation and transcriptomic analysis of hepatocytes captured by laser micro-dissection. We observe a deep link between epigenetic zonation of human liver and a zonated expression of metabolic and morphogenic pathways: Key transcriptionally zonated enzymes in xenobiotic and ...

Histopathological analysis of human biopsies. To quantitatively characterize the transition from simple STEA to eNASH, we stained, imaged and digitally reconstructed human liver tissue in 2D and 3D from biopsies of 25 patients classified into four groups: normal control (NC, n = 6), healthy obese (HO, n = 4), steatosis (STEA, n = 8) and eNASH (n = 7).

The study comprises 19 human liver biopsy donors divided into the groups normal control (NC = 7012, 7173, 7194, 7279), healthy obese (HO = 6758, 6922, 7213, 7230, 7252), bland steatosis (STEA = 6967, 7137, 7172, 7181, 7251) and early NASH (EARLY = 6610, 7041, 7157, 7188, 7344).

Hepatocytes captured by laser microdissection were obtained from three hepatic zones (pericentral, intermediate and periportal) and subjected to reduced representation bisulfite sequencing and RNA-seq resulting in 114 ...

Transcriptomic analysis of hepatocytes captured by laser micro-dissection from hepatic zone: pericentral (CV)

DNA-methylation at binding sites of uniformly expressed transcription factors in human hepatocytes ; hepatic zone: pericentral (CV)

Transcriptomic analysis of hepatocytes captured by laser micro-dissection from hepatic zone: intermediate (IZ)

Transcriptomic analysis of hepatocytes captured by laser micro-dissection from hepatic zone: periportal (PP)

DNA-methylation at binding sites of uniformly expressed transcription factors in human hepatocytes ; hepatic zone: intermediate (IZ)

DNA-methylation at binding sites of uniformly expressed transcription factors in human hepatocytes ; periportal (PP)

Experimental assay Human-NAFLD/HO , 4 biopsies from healthy obese patients. Samples for the HO category were obtained in patients undergoing bariatric surgery with a BMI > 30 and subgroups defined by liver histology as follows: HO samples showed a normal liver histology such as the NC samples.

-h692a -h6758 -h6922 -h7230

All file here

Files can be opened and visualised with http://motiontracking.mpi-cbg.de/get/ software

Experimental assay Human-NAFLD/NC 6 biopsies from normal control patients. : NC samples showed steatosis ≤5%, no inflammation, no ballooning and no fibrosis and were obtained during liver resections or biopsy in non-hepatobiliary malignancy in patients with a BMI<30kg/m2. Livers were either free of metastases or a distance of at least 2 cm to the next metastasis observed.

Image data for this assay available via link to file folder containing ...

Experimental assay Human-NAFLD/STEA 8 biopsies from steatosis patients. Samples for the STEA category were obtained in patients undergoing bariatric surgery with a BMI > 30 and subgroups defined by liver histology as follows: STEA samples had >5% fat, no inflammation, fibrosis ≤1 and ballooning ≤1.

Image data for this assay available via link to file folder containing image data for listed patient IDs (patientID in a file name)

...

Experimental assay Human-NAFLD/eNASH Samples for the eNASH category were obtained in patients undergoing bariatric surgery with a BMI > 30 and subgroups defined by liver histology as follows: eNASH samples were characterized by >5% fat, an inflammation grade of at least 1, fibrosis ≤1 and ballooning ≤1.

Image data for this assay available via link to file folder containing image data for listed patient IDs (patientID in a file name) ...

Human RNA-Seq data set GSM2819712 stored in NCBI (GEO)

Human RNA-Seq data set GSM2819698 stored in NCBI (GEO)

liver tissue sample : 6922_IZ_RNA

Human RNA-Seq data set GSM2819714 stored in NCBI (GEO)

Human RNA-Seq data set GSM2819713 stored in NCBI (GEO)

Human RNA-Seq data set GSM2819711 stored in NCBI (GEO)

Human RNA-Seq data set GSM2819710 stored in NCBI (GEO)

Human RNA-Seq data set GSM2819709 stored in NCBI (GEO)

Human RNA-Seq data set GSM2819695 stored in NCBI (GEO)

Human RNA-Seq data set GSM2819694 stored in NCBI (GEO)

The model is adapted from A.P. Kupinski, I. Raabe, M. Michel, D. Ail, L. Brusch, T. Weidemann, C. Bökel (2013) Phosphorylation of the Smo tail is controlled by membrane localization and is dispensable for clustering, J. Cell Sci., 126, 20, 4684-4697 https://doi.org/10.1242/jcs.128926

The model format is MorpheusML that can readily be loaded and run in Morpheus: https://morpheus.gitlab.io

Model for the interaction of Wnt and Hh as published in Kolbe et al.: Mutual Zonated Interactions of Wnt and Hh Signaling Are Orchestrating the Metabolism of the Adult Liver in Mice and Human, Cell Reports, 29,4553,

https://doi.org/10.1016/j.celrep.2019.11.104

For the spatio-temporal dynamics of bile transport, bile canalicular dilation, mechanical stimulation and transduction of YAP signaling during liver regeneration see the open access publication and its appendix: Meyer et al. (2020) Bile canaliculi remodeling activates YAP via the actin cytoskeleton during liver regeneration. Molecular Systems Biology 16:e8985. https://doi.org/10.15252/msb.20198985

The model format is MorpheusML that can readily be loaded and run in the free and open source software ...

Morpheus is the modelling and simulation framework for multicellular systems biology developed at Technische Universität Dresden. Manual, examples and binaries for Windows, Linux, MacOS at: https://morpheus.gitlab.io Open source code at: https://gitlab.com/morpheus.lab/morpheus

Code for the bile flow model in Segovia-Miranda et al.: Three-dimensional spatially resolved geometrical and functional models of human liver tissue reveal new aspects of NAFLD progression (https://www.nature.com/articles/s41591-019-0660-7)

See the README file in the link for details installing and running the code.

This model describes a core process during endocytosis. Intracellular vesicles called early endosomes contain the endocytosed cargo, e.g. signaling components like growth factors and RTKs, pathogens like viruses and nutrients like iron in transferrin. Early endosomes form an interacting pool of thousands of vesicles and jointly constitute the sorting and transport machinery in the endocytic pathway. Together with the cargo, membrane components travel to other compartments of the pathway which ...

SOP : liver tissue microdissection for RNA sequencing

Talk at the Jamboree 2021 about epigenomic map of human liver zonation and loss of zonation in end-stage liver disease

Computational modeling and simulation become increasingly important for Systems Medicine. A number of corresponding software tools have been developed but require scientists to encode their models in an imperative programming language. Morpheus [1,2], on the other hand, is an extensible open-source software framework that is entirely based on declarative modeling. It uses the domain-specific language MorpheusML to define multicellular models through a user-friendly GUI and has since proven ...

Shotgun lipidomics of microdissected periportal and pericentral zones; Characterization of NAFLD in Human Liver Biopsies by Shotgun Lipidomics

The meeting will provide a great opportunity for discussion between modellers, experimentalists and clinicians and to organize and harmonize our future work within the LiSyM network on the grassroot level.

This summit will cover both the basic and translational / clinical aspects of NAFLD, with a specific focus on novel drug target and prognostic signature development.

Key sessions include all crucial pathophysiological aspects currently known to affect development and progression of NAFLD, such as "lipid metabolism and lipotoxicity" and "insulin resistance, insulin and hormonal signaling". Furthermore, oxidative stress, ER stress, and mitochondrial dysfunction will be addressed. On the second day, ...

ICSB continues to be the flagship conference of the International Society for Systems Biology (ISSB). The conference will cover a variety of themes from Fundamental Biological Sciences, Network Analysis, to Metabolic Engineering and Cancer Biology. The conference will also include a variety of engaging plenary lectures, parallel sessions, poster sessions, and interactive networking opportunities.

Abstract submission deadline: May 13th, 2017

The International Conference on Systems Biology of Human Disease (SBHD) is a transatlantic event and communication platform for scientific exchange that takes place alternately between the United States and Germany.

SBHD 2017 is continuing a conference series launched by Peter Sorger and colleagues from Harvard Medical School in 2008. The conference focus is on mammalian systems biology, particularly on its application to human disease and therapy.

This event is a jointly organized Data Management PALs Meeting that involves PALs from the German LiSyM (Liver Systems Medicine) network and from the ERASysAPP (ERA-Net for Systems Biology Applications) initiative. PALs (Project Area Liaisons) are the front line experts of the data management teams of these projects. They act as data management advocates and help gathering user requirements and testing potential data management solutions. An important part of the meeting will be to gather the ...

Human microdissected liver tissue sample

Histopathology of human liver biopsies