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Transcriptional Dynamics of Hepatic Sinusoid‐Associated Cells After Liver Injury
Author(s) -
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
Publication year - 2020
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.31215
Subject(s) - hepatic stellate cell , sinusoid , biology , liver injury , fibrosis , myofibroblast , kupffer cell , hepatic fibrosis , pericyte , microbiology and biotechnology , crosstalk , cell type , pathogenesis , population , transcriptome , gene signature , liver cytology , cell , pathology , gene expression , immunology , gene , medicine , endothelial stem cell , endocrinology , genetics , physics , environmental health , optics , liver metabolism , in vitro
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.