Resolving the fibrotic niche of human liver cirrhosis at single-cell level

Research output: Contribution to journalArticlepeer-review

Authors

  • P Ramachandran
  • R Dobie
  • J R Wilson-Kanamori
  • E F Dora
  • B E P Henderson
  • J R Portman
  • K P Matchett
  • M Brice
  • J A Marwick
  • R S Taylor
  • M Efremova
  • R Vento-Tormo
  • N O Carragher
  • T J Kendall
  • J A Fallowfield
  • E M Harrison
  • D J Mole
  • S J Wigmore
  • J P Iredale
  • F Tacke
  • J W Pollard
  • C P Ponting
  • J C Marioni
  • S A Teichmann
  • N C Henderson

Colleges, School and Institutes

External organisations

  • MRC Centre for Inflammation Research and Royal Infirmary, University of Edinburgh, Edinburgh, UK.
  • NIHR Birmingham Biomedical Research Centre, University of Birmingham and University Hospitals Birmingham NHS Foundation Trust
  • University of Birmingham, Birmingham, UK
  • University of Edinburgh, The
  • Wellcome Sanger Institute
  • Edinburgh Genomics, University of Edinburgh
  • Beacon House and National Institute for Health Research
  • Department of Internal Medicine I (K.L., K.W., B.H., B.A., S.H.), University Hospital Würzburg, 97080 Würzburg, Germany; Clinical Endocrinology (M.Q.), Charité Campus Mitte, Charité University Medicine Berlin, 10117 Berlin, Germany; Medizinische Klinik und Poliklinik IV (A.S.D., M.R.), University Hospital Munich, 80336 Munich, Germany; Institute of Clinical Chemistry and Laboratory Medicine (H.W., A.H., N.F.), University Medicine Greifswald, 17489 Greifswald, Germany; Private Practice Endocrinology (H.W.), 99084 Erfurt, Germany; Department of Nephrology, Medical Faculty (L.C.R., I.Q.), Heinrich-Heine University Düesseldorf, 40225 Düsseldorf, Germany; and Department of Endocrinology and Metabolism (H.S.W.), Rostock University Medical Center, 18147 Rostock, Germany; Comprehensive Cancer Center Mainfranken & Department of Medicine I (C.T.F.), University of Wuerzburg, 97080 Wuerzburg, Germany.
  • Albert Einstein College of Medicine
  • Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge Cambridge Experimental Cancer Medicine Centre and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.

Abstract

Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2+CD9+ subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1+ and PLVAP+ endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFRα+ collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis.

Details

Original languageEnglish
Pages (from-to)512-518
Number of pages7
JournalNature
Volume575
Issue number7783
Publication statusPublished - Nov 2019

Keywords

  • Animals, Case-Control Studies, Cell Lineage, Duffy Blood-Group System/metabolism, Endothelial Cells/metabolism, Female, Hepatic Stellate Cells/cytology, Hepatocytes/cytology, Humans, Liver/cytology, Liver Cirrhosis/genetics, Macrophages/metabolism, Male, Membrane Glycoproteins/metabolism, Membrane Proteins/metabolism, Mice, Phenotype, Receptor, Platelet-Derived Growth Factor alpha/metabolism, Receptors, Cell Surface/metabolism, Receptors, Immunologic/metabolism, Single-Cell Analysis, Tetraspanin 29/metabolism, Transcriptome, Transendothelial and Transepithelial Migration