Transcriptional Dynamics of Hepatic Sinusoid‐Associated Cells After Liver Injury

• Published in: Hepatology (Baltimore, Md.) Vol. 72; no. 6; pp. 2119 - 2133
• Main Authors: Terkelsen, Mike K., Bendixen, Sofie M., Hansen, Daniel, Scott, Emma A.H., Moeller, Andreas F., Nielsen, Ronni, Mandrup, Susanne, Schlosser, Anders, Andersen, Thomas L., Sorensen, Grith L., Krag, Aleksander, Natarajan, Kedar N., Detlefsen, Sönke, Dimke, Henrik, Ravnskjaer, Kim
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.12.2020; John Wiley and Sons Inc
• Subjects: Animals; Biopsy; Capillaries - cytology; Capillaries - pathology; Carbon Tetrachloride - administration & dosage; Carbon Tetrachloride - toxicity; Cell activation; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - pathology; Disease Models, Animal; Endothelial cells; Endothelial Cells - pathology; Endothelium, Vascular - cytology; Endothelium, Vascular - pathology; Female; Fibrosis; Gene Regulatory Networks; Genes; Hepatic Veins - cytology; Hepatic Veins - pathology; Hepatocytes; Hepatology; Humans; Kupffer cells; Liver; Liver - blood supply; Liver - pathology; Liver Cirrhosis - genetics; Liver Cirrhosis - pathology; Liver diseases; Membrane Proteins - genetics; Mice; Mice, Transgenic; Non-alcoholic Fatty Liver Disease - pathology; Oligonucleotide Array Sequence Analysis; Original; Plasma membranes; RNA-Seq; Single-Cell Analysis; Stellate cells; Transcription
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.31215

Background and Aims Hepatic sinusoidal cells are known actors in the fibrogenic response to injury. Activated hepatic stellate cells (HSCs), liver sinusoidal endothelial cells, and Kupffer cells are responsible for sinusoidal capillarization and perisinusoidal matrix deposition, impairing vascular exchange and heightening the risk of advanced fibrosis. While the overall pathogenesis is well understood, functional relations between cellular transitions during fibrogenesis are only beginning to be resolved. At single‐cell resolution, we here explored the heterogeneity of individual cell types and dissected their transitions and crosstalk during fibrogenesis. Approach and Results We applied single‐cell transcriptomics to map the heterogeneity of sinusoid‐associated cells in healthy and injured livers and reconstructed the single‐lineage HSC trajectory from pericyte to myofibroblast. Stratifying each sinusoidal cell population by activation state, we projected shifts in sinusoidal communication upon injury. Weighted gene correlation network analysis of the HSC trajectory led to the identification of core genes whose expression proved highly predictive of advanced fibrosis in patients with nonalcoholic steatohepatitis (NASH). Among the core members of the injury‐repressed gene module, we identified plasmalemma vesicle–associated protein (PLVAP) as a protein amply expressed by mouse and human HSCs. PLVAP expression was suppressed in activated HSCs upon injury and may hence define hitherto unknown roles for HSCs in the regulation of microcirculatory exchange and its breakdown in chronic liver disease. Conclusions Our study offers a single‐cell resolved account of drug‐induced injury of the mammalian liver and identifies key genes that may serve important roles in sinusoidal integrity and as markers of advanced fibrosis in human NASH.