TY - JOUR
T1 - Single cell-resolved study of advanced murine MASH reveals a homeostatic pericyte signaling module
AU - Bendixen, Sofie M.
AU - Jakobsgaard, Peter R.
AU - Hansen, Daniel
AU - Hejn, Kamilla H.
AU - Terkelsen, Mike K.
AU - Bjerre, Frederik A.
AU - Thulesen, Annemette P.
AU - Eriksen, Niels G.
AU - Hallenborg, Philip
AU - Geng, Yana
AU - Dam, Trine V.
AU - Larsen, Frederik T.
AU - Wernberg, Charlotte W.
AU - Vijayathurai, Janusa
AU - Scott, Emma A.H.
AU - Marcher, Ann Britt
AU - Detlefsen, Sönke
AU - Grøntved, Lars
AU - Dimke, Henrik
AU - Berdeaux, Rebecca
AU - de Aguiar Vallim, Thomas Q.
AU - Olinga, Peter
AU - Lauridsen, Mette M.
AU - Krag, Aleksander
AU - Blagoev, Blagoy
AU - Ravnskjaer, Kim
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2024/3
Y1 - 2024/3
N2 - 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: The fibrogenic activation of hepatic stellate cells (HSCs) led to deterioration of a signaling module consisting of the bile acid receptor NR1H4/FXR and HSC-specific GS-protein-coupled receptors (GSPCRs) 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: We conclude that HSC-expressed NR1H4 and GSPCRs 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.
AB - 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: The fibrogenic activation of hepatic stellate cells (HSCs) led to deterioration of a signaling module consisting of the bile acid receptor NR1H4/FXR and HSC-specific GS-protein-coupled receptors (GSPCRs) 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: We conclude that HSC-expressed NR1H4 and GSPCRs 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.
KW - Bile Acids
KW - Cyclic AMP
KW - G-Protein-Coupled Receptors
KW - Hepatic Stellate Cells
KW - Inflammation
KW - Metabolic dysfunction-associated Steatohepatitis
KW - Nuclear Receptors
KW - Pericytes
KW - ScRNAseq
KW - Sinusoids
KW - Transcriptome
UR - http://www.scopus.com/inward/record.url?scp=85180557573&partnerID=8YFLogxK
U2 - 10.1016/j.jhep.2023.11.001
DO - 10.1016/j.jhep.2023.11.001
M3 - Article
C2 - 37972658
AN - SCOPUS:85180557573
SN - 0168-8278
VL - 80
SP - 467
EP - 481
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 3
ER -