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Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics

View ORCID ProfileP Ramachandran, R Dobie, JR Wilson-Kanamori, EF Dora, BEP Henderson, RS Taylor, KP Matchett, JR Portman, M Efremova, R Vento-Tormo, NT Luu, View ORCID ProfileCJ Weston, PN Newsome, View ORCID ProfileEM Harrison, View ORCID ProfileDJ Mole, SJ Wigmore, JP Iredale, F Tacke, JW Pollard, View ORCID ProfileCP Ponting, JC Marioni, SA Teichmann, View ORCID ProfileNC Henderson
doi: https://doi.org/10.1101/766113
P Ramachandran
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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  • For correspondence: Prakash.Ramachandran@ed.ac.uk Neil.Henderson@ed.ac.uk
R Dobie
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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JR Wilson-Kanamori
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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EF Dora
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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BEP Henderson
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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RS Taylor
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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KP Matchett
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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JR Portman
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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M Efremova
2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
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R Vento-Tormo
2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
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NT Luu
3National 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, Birmingham, UK
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CJ Weston
3National 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, Birmingham, UK
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PN Newsome
3National 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, Birmingham, UK
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EM Harrison
4Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK
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DJ Mole
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
4Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK
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SJ Wigmore
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
4Clinical Surgery, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK
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JP Iredale
5Senate House, University of Bristol, Bristol, UK
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F Tacke
6Department of Hepatology and Gastroenterology, Charité University Medical Center, Berlin, Germany
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JW Pollard
7MRC Centre for Reproductive Health, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
8Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, New York, USA
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CP Ponting
9MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK
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JC Marioni
2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
10European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, Cambridge, UK
11Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK
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SA Teichmann
2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK
11Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, UK
12Theory of Condensed Matter Group, The Cavendish Laboratory, University of Cambridge, JJ Thomas Ave, Cambridge, CD3 0EH, UK
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NC Henderson
1Centre for Inflammation Research, The Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
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  • ORCID record for NC Henderson
  • For correspondence: Prakash.Ramachandran@ed.ac.uk Neil.Henderson@ed.ac.uk
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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.

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Posted September 12, 2019.
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Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics
P Ramachandran, R Dobie, JR Wilson-Kanamori, EF Dora, BEP Henderson, RS Taylor, KP Matchett, JR Portman, M Efremova, R Vento-Tormo, NT Luu, CJ Weston, PN Newsome, EM Harrison, DJ Mole, SJ Wigmore, JP Iredale, F Tacke, JW Pollard, CP Ponting, JC Marioni, SA Teichmann, NC Henderson
bioRxiv 766113; doi: https://doi.org/10.1101/766113
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Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics
P Ramachandran, R Dobie, JR Wilson-Kanamori, EF Dora, BEP Henderson, RS Taylor, KP Matchett, JR Portman, M Efremova, R Vento-Tormo, NT Luu, CJ Weston, PN Newsome, EM Harrison, DJ Mole, SJ Wigmore, JP Iredale, F Tacke, JW Pollard, CP Ponting, JC Marioni, SA Teichmann, NC Henderson
bioRxiv 766113; doi: https://doi.org/10.1101/766113

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