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

By P. Ramachandran, R. Dobie, J. Wilson-Kanamori, Elena Dorà, Beth E. P. Henderson, N. Luu, J. R. Portman, Kylie P. Matchett, M. Brice, John A. Marwick and 19 more. Nature, 2019

1,426 citations recorded by the source corpus.

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. Single-cell RNA sequencing is used to characterize and compare the functional diversity of cells from liver biopsies of human scarred and normal liver, and identifies markers for scar-associated macrophages and endothelial cells.

Subfields: Epidemiology, Hepatology

View Paper: https://www.semanticscholar.org/paper/3b48bc303ca03af9a0b5c6a153e5489e3326acfb

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Epidemiology

1. Natascha Roehlen
2. E. Crouchet
3. T. Baumert

In Hepatology

1. Natascha Roehlen
2. E. Crouchet
3. T. Baumert

Citations in the corpus

• Spatial proteogenomics reveals distinct and evolutionarily conserved hepatic macrophage niches (2022, neutral): “Remaining liver cells (leukocytes, LSECs and HSCs; in vivo protocol) and total cells from the ex vivo digests were centrifuged at 400g for 5mins before proceeding to antibody staining for flow cytometry.”
• Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives (2020, background): “elegantly demonstrated that distinct macrophage subpopulations inhabit the fibrotic niche [238].”