Abstract
BackgroundLiver fibrosis is a wound-healing response to tissue injury and inflammation hallmarked by the extracellular matrix (ECM) protein deposition in the liver parenchyma and tissue remodelling. Different cell types of the liver are known to play distinct roles in liver injury response. Hepatocytes and liver endothelial cells receive molecular signals indicating tissue injury and activate hepatic stellate cells which produce ECM proteins upon their activation. Despite the growing knowledge on the molecular mechanism underlying hepatic fibrosis in general, the cell-type-specific gene regulatory network associated with the initial response to hepatotoxic injury is still poorly characterized.ResultsIn this study, we used thioacetamide (TAA) to induce hepatic injury in adult zebrafish. We isolated three major liver cell types - hepatocytes, endothelial cells and hepatic stellate cells - and identified cell-type-specific chromatin accessibility and transcriptional changes in an early stage of liver injury. We found that TAA induced transcriptional shifts in all three cell types hallmarked by significant alterations in the expression of genes related to fatty acid and carbohydrate metabolism, as well as immune response-associated and vascular-specific genes. Interestingly, liver endothelial cells exhibit the most pronounced response to liver injury at the transcriptome and chromatin level, hallmarked by the loss of their angiogenic phenotype.ConclusionOur results uncovered cell-type-specific transcriptome and epigenome responses to early stage liver injury, which provide valuable insights into understanding the molecular mechanism implicated in the early response of the liver to pro-fibrotic signals.
Highlights
Liver fibrosis is a wound-healing response to tissue injury and inflammation hallmarked by the extracellular matrix (ECM) protein deposition in the liver parenchyma and tissue remodelling
Whole livers were dissected from adult zebrafish from each of the transgenic lines used in this study (Fig. 1A)
Gene ontology (GO) analysis revealed the enrichment of genes related to angiogenesis in Endothelial cell (EC), insulin-like growth factor receptor signalling genes and cellular phosphate ion homeostasis in HEPs and lipid transport and metabolism genes in hepatic stellate cells (HSC) (Fig. 2C)
Summary
Liver fibrosis is a wound-healing response to tissue injury and inflammation hallmarked by the extracellular matrix (ECM) protein deposition in the liver parenchyma and tissue remodelling. Despite the growing knowledge on the molecular mechanism underlying hepatic fibrosis in general, the cell-typespecific gene regulatory network associated with the initial response to hepatotoxic injury is still poorly characterized. Its increasing prevalence leads to an expanding body of work regarding the molecular mechanisms present in advanced liver disease, our knowledge about the earliest stages of liver injury is still limited. The predominant causes of liver fibrosis are chronic excessive alcohol consumption, viral hepatitis B and C and non-alcoholic fatty liver disease (NAFLD), the latter becoming a major concern with the increasing incidence of obesity in Europe and the USA [1]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
