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

التفاصيل البيبلوغرافية
العنوان: Single cell-resolved study of advanced murine MASH reveals a homeostatic pericyte signaling module.
المؤلفون: Bendixen SM; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Jakobsgaard PR; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Hansen D; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Hejn KH; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Terkelsen MK; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Bjerre FA; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Thulesen AP; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Eriksen NG; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Hallenborg P; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Geng Y; Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, the Netherlands., Dam TV; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Larsen FT; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Wernberg CW; Department of Gastroenterology and Hepatology, Odense University Hospital, Denmark; Department of Gastroenterology and Hepatology, University Hospital of South Denmark Esbjerg, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Vijayathurai J; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Scott EAH; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Marcher AB; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Detlefsen S; Department of Pathology, Odense University Hospital, Denmark; Department of Clinical Research, University of Southern Denmark, Denmark., Grøntved L; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Dimke H; Department of Molecular Medicine, University of Southern Denmark, Denmark; Department of Nephrology, Odense University Hospital, Denmark., Berdeaux R; Department of Integrative Biology and Pharmacology, McGovern Medical School, UT Health Houston, USA., de Aguiar Vallim TQ; Department of Medicine, Division of Cardiology, University of California, Los Angeles, USA; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, USA., Olinga P; Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, the Netherlands., Lauridsen MM; Department of Gastroenterology and Hepatology, University Hospital of South Denmark Esbjerg, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Krag A; Department of Gastroenterology and Hepatology, Odense University Hospital, Denmark; Department of Clinical Research, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Blagoev B; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark., Ravnskjaer K; Department of Biochemistry and Molecular Biology, University of Southern Denmark, Denmark; Center for Functional Genomics and Tissue Plasticity, University of Southern Denmark, Denmark. Electronic address: ravnskjaer@bmb.sdu.dk.
المصدر: Journal of hepatology [J Hepatol] 2024 Mar; Vol. 80 (3), pp. 467-481. Date of Electronic Publication: 2023 Nov 14.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8503886 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1600-0641 (Electronic) Linking ISSN: 01688278 NLM ISO Abbreviation: J Hepatol Subsets: MEDLINE
أسماء مطبوعة: Publication: 2001- : Amsterdam : Elsevier
Original Publication: Copehnagen : Munksgaard International Publishers, [c1984-
مواضيع طبية MeSH: Diabetes Mellitus, Type 2*/metabolism , Fatty Liver*/metabolism, Mice ; Humans ; Animals ; Pericytes/metabolism ; Liver/pathology ; Signal Transduction ; Hepatic Stellate Cells/metabolism ; Liver Cirrhosis/pathology ; Growth Differentiation Factor 2/metabolism
مستخلص: 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 G S -protein-coupled receptors (G S 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: We conclude that HSC-expressed NR1H4 and G S 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.
Competing Interests: Conflict of interest The authors declare no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details.
(Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
فهرسة مساهمة: Keywords: Bile Acids; Cyclic AMP; G-Protein-Coupled Receptors; Hepatic Stellate Cells; Inflammation; Metabolic dysfunction-associated Steatohepatitis; Nuclear Receptors; Pericytes; ScRNAseq; Sinusoids; Transcriptome
المشرفين على المادة: 0 (Gdf2 protein, mouse)
0 (Growth Differentiation Factor 2)
تواريخ الأحداث: Date Created: 20231116 Date Completed: 20240219 Latest Revision: 20240219
رمز التحديث: 20240219
DOI: 10.1016/j.jhep.2023.11.001
PMID: 37972658
قاعدة البيانات: MEDLINE
الوصف
تدمد:1600-0641
DOI:10.1016/j.jhep.2023.11.001