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

Ramachandran, P and Dobie, R and Wilson-Kanamori, J R and Dora, E F and Henderson, B E P and Luu, N T and Portman, J R and Matchett, K P and Brice, M and Marwick, J A and Taylor, R S and Efremova, M and Vento-Tormo, R and Carragher, N O and Kendall, T J and Fallowfield, J A and Harrison, E M and Mole, D J and Wigmore, S J and Newsome, P N and Weston, C J and Iredale, J P and Tacke, F and Pollard, J W and Ponting, C P and Marioni, J C and Teichmann, S A and Henderson, N C (2019) Resolving the fibrotic niche of human liver cirrhosis at single-cell level. Nature. ISSN 1476-4687. (Submitted)

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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 TREM2CD9 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.

Item Type: Article
Subjects: WI Digestive system. Gastroenterology
Divisions: Planned IP Care > Gastroentrology
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Depositing User: Mrs Yolande Brookes
Date Deposited: 11 Oct 2019 14:36
Last Modified: 11 Oct 2019 14:36

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