Single cell-resolved study of advanced murine MASH reveals a homeostatic pericyte signaling module

Here we profile the transcripts of app. 32.000 single cells isolated from livers of healthy mice fed with a chow diet and diseased mice fed with a western diet for 52 weks. We analyzed the fibrogenic transition of HSCs from pericytes to collagen-producing cells, interrogated the NASH-associated rerouting of mononuclear phagocytes and uncovered novel aspects of cellular palsticity during more advanced stages of NASH. We reveal Stellate cell-specific Gs-protein-coupled receptors and the bile-acid receptor NR1H4/FXR seemingly dominated HSC biology in the healthy liver, forming the basis for multimodal diurnal signaling, but deteriorated in activated HSCs in advanced NASH. In addition to two emerging populations of Trem2-expressing monocyte-derived macrophages we found a population of CD207-positive macrophages significantly expanded in advanced NASH and likely derived from both incoming monocytes and Kupffer cells. Our work illustrates the emmense plasticity liver cells undergo upon induction of NASH, and potentially map novel treatment targets Overall design: Here we performed gene expression profiling analysis of primary hepatic stellate cells (in vitro) using data obtained from RNA-seq of cells treated with a combination of either Obeticholic acid (OCA) (3h) + Vasoactive intestinal peptide (VIP) (3 hour), or DMSO (3 hour) + VIP (3 hour)