Transcriptional Dynamics of Hepatic Sinusoid‐Associated Cells After Liver Injury

Abstract

Background & 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 & Results: We applied single-cell transcriptomics to map the heterogeneity of sinusoid-associated cells in healthy and injured livers and reconstructed the singlelineage HSC trajectory from pericyte to myofibroblast. Stratifying each sinusoidal cell population by activation state, we projected shifts in sinusoidal communication upon injury. Weighted Gene Co-Expression Network Analysis of the HSC trajectory led to the identification of core genes, whose expression proved highly predictive of advanced fibrosis in NASH patients. 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 advance fibrosis in human NASH.

The Genetic Architecture of Carbon Tetrachloride-Induced Liver Fibrosis in Mice

“… 29 In addition, 48 of these 300 genes were identified as top HSC state-defining genes during a CCl 4 treatment time course study in C57BL/6J mice. 30 …”

Osteoprotegerin Is more than a Possible Serum Marker in Liver Fibrosis: A Study into Its Function in Human and Murine Liver

“…Generation of these data has been described before [32]. In short, female C57BL6/J mice were treated with vehicle or CCl 4 for 2 or 4 weeks (n = 3).…”

Level of MFAP4 in ascites independently predicts 1-year transplant-free survival in patients with cirrhosis

“… 15 , 16 A recent single-cell RNA-sequencing study showed that MFAP4 secreted by hepatic stellate cells was an integral part of the transcriptome in murine models of liver fibrosis and confirmed the MFAP4 gene as 1 of 4 hepatic expressed genes that are robust predictors of advanced fibrosis. 17 Observational follow-up studies of early-stage liver disease have shown that fibrosis is the most important prognostic factor in liver disease. 18 , 19 Biomarkers of liver fibrosis may therefore also provide prognostic information.…”