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

• Published in: Nature (London) Vol. 575; no. 7783; pp. 512 - 518
• Main Authors: Ramachandran, P., Dobie, R., Wilson-Kanamori, J. R., Dora, E. F., Henderson, B. E. P., Luu, N. T., Portman, J. R., Matchett, K. P., Brice, M., Marwick, J. A., Taylor, R. S., Efremova, M., Vento-Tormo, R., Carragher, N. O., Kendall, T. J., Fallowfield, J. A., Harrison, E. M., Mole, D. J., Wigmore, S. J., Newsome, P. N., Weston, C. J., Iredale, J. P., Tacke, F., Pollard, J. W., Ponting, C. P., Marioni, J. C., Teichmann, S. A., Henderson, N. C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.11.2019; Nature Publishing Group
• Subjects: 13/106; 13/31; 13/51; 14/19; 38/32; 38/91; 631/1647/2217/2018; 631/250/2504/342/1591; 631/80/304; 692/699/1503/1607/1604; 692/699/1503/1607/1605; Analysis; Animals; Bioinformatics; Biological markers; Case-Control Studies; CD9 antigen; Cell Lineage; Cirrhosis; Collagen; Diagnosis; Duffy Blood-Group System - metabolism; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - pathology; Female; Fibrosis; Flow cytometry; Gene expression; Genetic aspects; Hepatic Stellate Cells - cytology; Hepatic Stellate Cells - metabolism; Hepatic Stellate Cells - pathology; Hepatocytes; Hepatocytes - cytology; Hepatocytes - metabolism; Hepatocytes - pathology; Humanities and Social Sciences; Humans; Identification and classification; Leukocytes; Liver; Liver - cytology; Liver - pathology; Liver cirrhosis; Liver Cirrhosis - genetics; Liver Cirrhosis - pathology; Liver diseases; Macrophages; Macrophages - metabolism; Macrophages - pathology; Male; Membrane Glycoproteins - metabolism; Membrane Proteins - metabolism; Mesenchyme; Methods; Mice; Molecular modelling; Monocytes; multidisciplinary; Open source software; Pathogenesis; Phenotype; Public domain; Quality control; Receptor, Platelet-Derived Growth Factor alpha - metabolism; Receptors, Cell Surface - metabolism; Receptors, Immunologic - metabolism; RNA sequencing; Scars; Science; Science (multidisciplinary); Signal transduction; Single-Cell Analysis; Tetraspanin 29 - metabolism; Therapeutic applications; Transcriptome; Transendothelial and Transepithelial Migration; Unicellular organisms; United Kingdom
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-019-1631-3

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.