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Interaction of neutrophils and hepatic stellate cells promotes fibrosis in a mouse model of steatohepatitis

ABSTRACT: Our current study proved a synergistic effect of obesity and binge drinking on liver fibrosis, which is partially mediated via the interaction of neutrophils and HSCs. Controlling the infiltration of neutrophils as well as the interplay between neutrophils and HSCs may be a novel therapeutic intervention to prevent liver fibrosis in steatohepatitis.

ORGANISM(S): Mus musculus

PROVIDER: GSE98153 | GEO | 2018/04/11

REPOSITORIES: GEO

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Glycolysis in hepatic stellate cells coordinates fibrogenic extracellular vesicle release spatially to amplify liver fibrosis

Project description:Liver fibrosis is characterized by the activation of perivascular hepatic stellate cells (HSCs), the release of fibrogenic nano-sized extracellular vesicles (EVs) and increased HSC glycolysis. Nevertheless, how glycolysis in HSCs coordinates fibrosis amplification through tissue zone-specific pathways remains elusive. Here, we demonstrate that HSC-specific genetic inhibition of glycolysis reduced liver fibrosis. Moreover, spatial transcriptomics revealed a fibrosis-mediated upregulation of EV-related pathways in the liver pericentral zone, which was abrogated by the glycolysis genetic inhibition. Mechanistically, glycolysis in HSCs upregulated the expression of EV-related genes such as RAB31 by enhancing histone-3-lysine-9 acetylation on the promoter region, which increased EV release. Functionally, these glycolysis-dependent EVs increased fibrotic gene expression in recipient HSC. Furthermore, EVs derived from glycolysis-deficient mice abrogated liver fibrosis amplification in contrast to glycolysis-competent mouse EVs. In summary, glycolysis in HSCs amplifies liver fibrosis by promoting fibrogenic EV release in the hepatic pericentral zone, which represents a potential therapeutic target.

2024-05-16 | PXD050337 | Pride

Human hepatic stellate cell-derived extracellular vesicles LC-MSMS

Project description:Activation and migration of hepatic stellate cells (HSCs) followed by matrix deposition are characteristics of liver fibrosis. Several studies have shown the importance of hepatocyte and endothelial cell-derived extracellular vesicles (EVs) in liver pathobiology. However, less is known about the role of HSC-derived EVs in liver diseases. In this study, we investigated the molecules released through HSC-derived EVs and whether these can promote fibrosis.

2018-10-18 | PXD007258 | Pride

Transcriptomic characterization of circulating neutrophils isolated from patients with metabolic dysfunction-associated steatohepatitis (MASH), formerly known as nonalcoholic steatohepatitis (NASH).

Project description:Neutrophils, a major innate immune cell population, are the most abundant circulating white blood cell in humans. They play a crucial role in host defense against infection; however, aberrant neutrophil activation may induce tissue damage via sterile inflammation. Neutrophil accumulation has been identified as a feature of the inflammatory response observed MASH and has been associated with liver fibrosis and cirrhosis. In the present study, we used RNA-Seq analysis of purified neutrophils to characterize their dysregulation in MASH.

2024-05-15 | GSE247467 | GEO

An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in non-alcoholic steatohepatitis

Project description:Advanced hepatic fibrosis, driven by the activation of hepatic stellate cells (HSCs), affects millions world-wide and is the strongest predictor of mortality in non-alcoholic steatohepatitis (NASH), yet there are no approved anti-fibrotic therapies. To identify novel anti-fibrotic drug targets, we integrated progressive transcriptomic and morphological responses that accompany HSC activation in advanced disease using single nuclear RNA sequencing and tissue clearing in a robust, murine NASH model. In advanced fibrosis, an autocrine HSC signaling circuit emerges that is comprised of 68 receptor-ligand interactions conserved between murine and human NASH. These predicted interactions are supported by the parallel appearance of markedly increased direct stellate cell-cell contacts in murine NASH. As proof of principle, pharmacological inhibition of one such autocrine interaction, NTRK3-NTF3, inhibits human HSC activation in culture and reverses advanced murine NASH-fibrosis in vivo. We have uncovered a novel repertoire of previously uncharacterized anti-fibrotic drug targets underlying advanced fibrosis in vivo. The findings suggest a novel therapeutic paradigm in which stage-specific therapies could yield enhanced anti-fibrotic efficacy in patients with advanced fibrosis.

2022-10-21 | GSE212837 | GEO

Single cell-resolved study of advanced murine NASH reveals a homeostatic stellate cell signaling module [HSCc_fsk_3h_bulkRNA]

Project description:Non-alcoholic steatohepatitis (NASH) is associated with hepatic steatosis, intralobular inflammation, and fibrosis. The degree of hepatic fibrosis, mainly caused by excessive production of extracellular matrix proteins, is the sole predictor of liver-related and overall mortality in NASH patients. The hepatic stellate cells (HSCs) are causally implicated in fibrogenesis during NASH development but as sinusoidal pericytes also vital for vascular homeostasis of the healthy liver. Using single-cell RNA-sequencing we have analyzed whole liver plasticity and interrogated the transition of HSCs from pericytes in the healthy liver to collagen-producing cells in a diet-induced murine model of advanced NASH. We show how postprandial cues are sensed and integrated by HSCs promoting their phenotypic stabilization and, through paracrine mediators, sinusoidal health. While dominant under healthy conditions the basis for this multimodal signaling through stellate cell-specific Gs protein-coupled receptors and the bile-acid receptor NR1H4/FXR deteriorates in activated HSCs of the NASH liver. Expression of key signaling components were validated in situ in human and murine liver tissue supporting the translatability of our findings and pharmacological relevance in treatment of chronic liver diseases as NASH.

2023-11-21 | GSE218294 | GEO

The molecular phenotypes of injury, steatohepatitis, and fibrosis in liver transplant biopsies in the INTERLIVER study

Project description:To extend previous molecular analyses of rejection in liver transplant biopsies in the INTERLIVER study (ClinicalTrials.gov #NCT03193151), the present study aimed to define the gene expression selective for parenchymal injury, fibrosis, and steatohepatitis. PC1 reflected parenchymal injury and related inflammation in the early posttransplant period, slowly regressing over many months. PC2 separated early injury from late fibrosis. Positive PC3 identified a distinct mildly inflamed state correlating with histologic steatohepatitis. Injury PCs correlated with liver function and histologic abnormalities. A classifier trained on histologic steatohepatitis predicted histologic steatohepatitis with cross-validated AUC=0.83, and was associated with pathways reflecting metabolic abnormalities distinct from fibrosis. PC2 predicted histologic fibrosis (AUC=0.80), as did a molecular fibrosis classifier (AUC=0.74). The fibrosis classifier correlated with matrix remodeling pathways with minimal overlap with those selective for steatohepatitis, although some biopsies had both. Genome-wide assessment of liver transplant biopsies can not only detect molecular changes induced by rejection but also those correlating with parenchymal injury, steatohepatitis, and fibrosis, offering potential insights into disease mechanisms for primary diseases.

2022-01-09 | GSE193135 | GEO

In vitro activation and reversion of human primary hepatic stellate cells

Project description:Liver fibrosis is characterized by the excessive formation and accumulation of matrix proteins as a result of wound healing in the liver. A main event during fibrogenesis is the activation of the liver resident quiescent hepatic stellate cell (qHSC). Recent studies suggest that reversion of the activated HSC (aHSC) phenotype into a quiescent-like phenotype could be a major cellular mechanism underlying fibrosis regression in the liver, thereby offering new therapeutic perspectives for the treatment of liver fibrosis. The goal of the present study is to identify experimental conditions that can revert the activated status of human HSCs and to map the molecular events associated with this phenotype reversion by gene expression profiling Transcriptomic profiling of primary human quiescent HSCs (qHSCs), in vitro activated HSCs (aHSCs) and in vitro reverted HSCs (rHSCs). The cell types come from different donors (This is detailed in the original manuscript.).

2015-08-12 | E-GEOD-68001 | biostudies-arrayexpress

Post-transplant (non-alcoholic steatohepatitis) NASH compared with transplanted normal controls

Project description:Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease that ranges from simple steatosis, to inflammatory form non-alcoholic steatohepatitis (NASH), cirrhosis, and up to hepatocellular carcinoma. While NASH usually takes decades to develop at a rate of one stage per seven years, in the case of post-trasplant NASH (pt-NASH) develops fibrosis much more rapidly, with almost 50% of liver transplant recipients presenting stage 3 fibrosis by 5 years post-transplant. Archived fresh-frozen transplanted liver biopsy samples from four liver biopsy samples with evidence of NASH (2 recurrent and 2 de novo), two with simple steatosis (both de novo), and five with normal histology as controls had their transcriptome sequenced in two batches for deeper coverage.

2022-05-09 | E-MTAB-11688 | biostudies-arrayexpress

O-GlcNAcylation controls pro-fibrotic transcriptional regulatory signaling in hepatic stellate cells

Project description:Liver injury causes “transdifferentiation” of quiescent hepatic stellate cells (Q-HSCs) into wound repairing myofibroblasts (MF-HSCs), whose uncontrolled activation leads ultimately to liver fibrosis. Although this process is triggered by deep metabolic and transcriptional reprogramming, functional links between these two key events are not yet understood. Here, using a compendium of in vitro, ex vivo and in vivo models of fibrogenic liver injuries in addition to human liver samples, we report that O-linked β D N acetylglucosaminylation (O GlcNAcylation), a post-translational modification (PTM) considered as nutritional sensor, is increased during myofibroblastic activation of HSCs and is required for their pro-fibrotic activities. Mechanistically, a multi omics approach combining proteomic, epigenomic and transcriptomic data mining revealed that O GlcNAcylation controls the transcriptional program of MF-HSCs by targeting the key fibrogenic transcription factors Basonuclin 2 (BNC2) and TEA domain transcription factor 4 (TEAD4) together with the Yes associated protein 1 (YAP1) co-activator. Indeed, inhibition of protein O GlcNAcylation impedes their stability leading to decreased functionality of the BNC2/TEAD4/YAP1 complex towards promoting activation of fibrogenic transcriptional regulatory elements. Altogether, this study unravels the fibrogenic role of protein O-GlcNAcylation identifying a vulnerable regulatory process in activated HSCs.

2024-05-21 | PXD045860 | Pride

AdipoR1/AdipoR2 dual agonist recovers nonalcoholic steatohepatitis and related fibrosis via endoplasmic reticulum-mitochondria axis

Project description:Nonalcoholic steatohepatitis (NASH) and associated liver fibrosis have limited therapy options. We report a novel adiponectin-based dual agonist for adiponectin receptors 1 and 2 with a longer half-life, and show that it ameliorates NASH and liver fibrosis in mouse models.

2020-10-03 | GSE158951 | GEO

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