TY - JOUR T1 - Resolving the fibrotic niche of human liver cirrhosis using single-cell transcriptomics JF - bioRxiv DO - 10.1101/766113 SP - 766113 AU - P Ramachandran AU - R Dobie AU - JR Wilson-Kanamori AU - EF Dora AU - BEP Henderson AU - RS Taylor AU - KP Matchett AU - JR Portman AU - M Efremova AU - R Vento-Tormo AU - NT Luu AU - CJ Weston AU - PN Newsome AU - EM Harrison AU - DJ Mole AU - SJ Wigmore AU - JP Iredale AU - F Tacke AU - JW Pollard AU - CP Ponting AU - JC Marioni AU - SA Teichmann AU - NC Henderson Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/09/12/766113.abstract N2 - 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. ER -