P Ramachandran, R Dobie, JR Wilson-Kanamori, EF Dora, BEP Henderson, NT Luu, JR Portman, KP Matchett, M Brice, JA Marwick, RS Taylor, M Efremova, R Vento-Tormo, NO Carragher, TJ Kendall, JA Fallowfield, EM Harrison, DJ Mole, SJ Wigmore, PN Newsome, CJ Weston, JP Iredale, F Tacke, JW Pollard, CP Ponting, JC Marioni, SA Teichmann, NC Henderson
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 human single cells, yielding molecular definitions for non-parenchymal cell types present in healthy and cirrhotic human liver. We uncover a novel scar-associated TREM2+CD9+ macrophage subpopulation, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define novel ACKR1+ and PLVAP+ endothelial cells that expand in cirrhosis, are topographically scar-restricted and enhance leucocyte transmigration. Multi-lineage ligand-receptor modelling of interactions between the novel 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 the conceptual framework required to discover rational therapeutic targets in liver cirrhosis.