Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics
Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics
Abstract Currently there are no effective antifibrotic therapies for liver cirrhosis, a major killer worldwide. To obtain a cellular resolution of directly-relevant pathogenesis and to inform therapeutic design, we profile the transcriptomes of over 100,000 primary human single cells, yielding molecular definitions for the major non-parenchymal cell types present in healthy and cirrhotic human liver. We uncover a novel scar-associated TREM2+CD9+ macrophage subpopulation with a fibrogenic phenotype, that has a distinct differentiation trajectory from circulating monocytes. In the endothelial compartment, we show that newly-defined ACKR1+ and PLVAP+ endothelial cells expand in cirrhosis and are topographically located in the fibrotic septae. Multi-lineage ligand-receptor modelling of specific interactions between the novel scar-associated macrophages, endothelial cells and collagen-producing myofibroblasts in the fibrotic niche, reveals intra-scar activity of several major pathways which promote hepatic fibrosis. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides the conceptual framework required to discover rational therapeutic targets in liver cirrhosis.
Mole DJ、Newsome PN、Harrison EM、Iredale JP、Wilson-Kanamori JR、Matchett KP、Luu NT、Tacke F、Ponting CP、Taylor RS、Wigmore SJ、Efremova M、Portman JR、Henderson BEP、Dora EF、Dobie R、Pollard JW、Henderson NC、Vento-Tormo R、Ramachandran P、Marioni JC、Teichmann SA、Weston CJ
Centre for Inflammation Research, The Queen?ˉs Medical Research Institute, University of Edinburgh||Clinical Surgery, University of Edinburgh, Royal Infirmary of EdinburghNational Institute for Health Research Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute for Immunology and Immunotherapy (III), Institute for Biomedical Research, University of BirminghamClinical Surgery, University of Edinburgh, Royal Infirmary of EdinburghSenate House, University of BristolCentre for Inflammation Research, The Queen?ˉs Medical Research Institute, University of EdinburghCentre for Inflammation Research, The Queen?ˉs Medical Research Institute, University of EdinburghNational Institute for Health Research Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute for Immunology and Immunotherapy (III), Institute for Biomedical Research, University of BirminghamDepartment of Hepatology and Gastroenterology, Charit¨| University Medical CenterMRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of EdinburghCentre for Inflammation Research, The Queen?ˉs Medical Research Institute, University of EdinburghCentre for Inflammation Research, The Queen?ˉs Medical Research Institute, University of Edinburgh||Clinical Surgery, University of Edinburgh, Royal Infirmary of EdinburghWellcome Sanger Institute, Wellcome Genome CampusCentre for Inflammation Research, The Queen?ˉs Medical Research Institute, University of EdinburghCentre for Inflammation Research, The Queen?ˉs Medical Research Institute, University of EdinburghCentre for Inflammation Research, The Queen?ˉs Medical Research Institute, University of EdinburghCentre for Inflammation Research, The Queen?ˉs Medical Research Institute, University of EdinburghMRC Centre for Reproductive Health, The Queen?ˉs Medical Research Institute, University of Edinburgh||Department of Developmental and Molecular Biology, Albert Einstein College of MedicineCentre for Inflammation Research, The Queen?ˉs Medical Research Institute, University of EdinburghWellcome Sanger Institute, Wellcome Genome CampusCentre for Inflammation Research, The Queen?ˉs Medical Research Institute, University of EdinburghWellcome Sanger Institute, Wellcome Genome Campus||European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI)||Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing CentreWellcome Sanger Institute, Wellcome Genome Campus||Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre||Theory of Condensed Matter Group, The Cavendish Laboratory, University of CambridgeNational Institute for Health Research Biomedical Research Unit and Centre for Liver and Gastrointestinal Research, Institute for Immunology and Immunotherapy (III), Institute for Biomedical Research, University of Birmingham
医学研究方法基础医学内科学
Mole DJ,Newsome PN,Harrison EM,Iredale JP,Wilson-Kanamori JR,Matchett KP,Luu NT,Tacke F,Ponting CP,Taylor RS,Wigmore SJ,Efremova M,Portman JR,Henderson BEP,Dora EF,Dobie R,Pollard JW,Henderson NC,Vento-Tormo R,Ramachandran P,Marioni JC,Teichmann SA,Weston CJ.Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics[EB/OL].(2025-03-28)[2025-05-12].https://www.biorxiv.org/content/10.1101/766113.点此复制
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