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

Research output: Contribution to journalArticle

  • P Ramachandran
  • R Dobie
  • J R Wilson-Kanamori
  • E F Dora
  • B E P Henderson
  • N T Luu
  • 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
  • P N Newsome
  • C J Weston
  • J P Iredalehttp://orcid.org/0000-0003-2174-5127
  • F Tacke
  • J W Pollard
  • C P Ponting
  • J C Marioni
  • S A Teichmann
  • N C Henderson
Original languageEnglish
Pages (from-to)512-518
Number of pages7
JournalNature
Volume575
Issue number7783
DOIs
DateAccepted/In press - 4 Sep 2019
DatePublished (current) - 9 Oct 2019

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.

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