Single cell-resolved study of advanced murine MASH reveals a homeostatic pericyte signaling module
Sofie M. Bendixen, Peter R. Jakobsgaard, Daniel Hansen, Kamilla H Hejn, Mike Krogh Terkelsen, Frederik Adam Bjerre, Annemette Præstegaard Thulesen, Niels G. Eriksen, Philip Hallenborg, Yana Geng, Trine V. Dam, Frederik T. Larsen, Charlotte Wilhelmina Wernberg, Janusa Vijayathurai, Emma A.H. Scott, Ann-Britt Marcher, Sönke Detlefsen, Lars Grøntved, Henrik Dimke, Rebecca Berdeaux, Thomas Q. de Aguiar Vallim, Peter Olinga, Mette Munk Lauridsen, Aleksander Krag, Blagoy Blagoev, Kim Ravnskjær
Abstract
BACKGROUND & AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) is linked to insulin resistance and type 2 diabetes and marked by hepatic inflammation, microvascular dysfunction, and fibrosis, impairing liver function and aggravating metabolic derangements. The liver homeostatic interactions disrupted in MASH are still poorly understood. We aimed to elucidate the plasticity and changing interactions of non-parenchymal cells associated with advanced MASH. METHODS: We characterized a diet-induced mouse model of advanced MASH at single-cell resolution and validated findings by assaying chromatin accessibility, bioimaging murine and human livers, and via functional experiments in vivo and in vitro. RESULTS: PCRs) capable of preserving stellate cell quiescence. Accompanying HSC activation, we further observed the attenuation of HSC Gdf2 expression, and a MASH-associated expansion of a CD207-positive macrophage population likely derived from both incoming monocytes and Kupffer cells. CONCLUSION: PCRs of the healthy liver integrate postprandial cues, which sustain HSC quiescence and, through paracrine signals, overall sinusoidal health. Hence HSC activation in MASH not only drives fibrogenesis but may desensitize the hepatic sinusoid to liver homeostatic signals. IMPACT AND IMPLICATIONS: Homeostatic interactions between hepatic cell types and their deterioration in metabolic dysfunction-associated steatohepatitis are poorly characterized. In our current single cell-resolved study of advanced murine metabolic dysfunction-associated steatohepatitis, we identified a quiescence-associated hepatic stellate cell-signaling module with potential to preserve normal sinusoid function. As expression levels of its constituents are conserved in the human liver, stimulation of the identified signaling module is a promising therapeutic strategy to restore sinusoid function in chronic liver disease.