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

By 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

Posted 12 Sep 2019
bioRxiv DOI: 10.1101/766113 (published DOI: 10.1038/s41586-019-1631-3)

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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