Identification of NASH-associated signaling networks in murine hepatic stellate cells

Research output: Contribution to conference without publisher/journalPosterResearch


The hepatic fibrosis score is the strongest predictor of disease-specific mortality in patients with non-alcoholic fatty liver disease. Hepatic fibrosis occurs as the disease progresses to non-alcoholic steatohepatitis (NASH) with hepatic inflammation and the appearance of fibrogenic myofibroblasts.
Activated hepatic stellate cells (HSCs) are the major source of collagen-producing myofibroblasts in NASH. Understanding the molecular pathways by which quiescent HSCs are activated and reprogrammed into myofibroblasts during NASH progression is hence key to improved diagnosis and targeted intervention in the development of fibrosis.
Here we present networks of NASH-associated factors in primary HSCs isolated from Western diet-fed mice. These factors and associated networks were identified using RNA-sequencing, novel time-course clustering algorithms, and network enrichment analyses. By topographically comparing changes in gene expression profiles across three experimental models of HSC activation we found core signaling nodes linking external signals to the reshaping of HSC morphology and function.
These regulated core nodes include cell surface receptors, putative signal transduction complexes, as well as downstream effectors. The significance of these as necessary drivers of HSC reprogramming is currently being validated experimentally.
This study demonstrates the power of combining time- and cell type-resolved transcriptomic analyses across different experimental models of HSC activation. It furthermore shows the usefulness of time-course clustering algorithms for identifying conserved, disease-associated gene sets with near-identical expression trajectories.
Our findings expose regulatory networks associated with phenotypic changes in primary murine HSCs during NASH development. Novel putative drivers of HSC reprogramming to hepatic myofibroblasts are currently being validated experimentally and could become attractive candidates for pharmacological intervention in the development of hepatic fibrosis.
Original languageEnglish
Publication date15. Oct 2017
Publication statusPublished - 15. Oct 2017
Event33rd Ernst Klenk Symposium in Molecular Medicine: Tissue regeneration, wound healing and fibrosis: Translating basic discoveries into patient survival. - CMMC, Cologne, Germany
Duration: 15. Oct 201717. Oct 2017


Conference33rd Ernst Klenk Symposium in Molecular Medicine


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