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Single-Cell Transcriptome Atlas Gives Peek at Cell Interactions in Liver Cirrhosis

NEW YORK – Researchers have generated a single-cell transcriptome atlas of liver cirrhosis.

About 844 million people around the globe have chronic liver disease, which leads to about 2 million deaths each year. To better understand the interactions between different cell lineages in liver fibrosis, researchers led by the University of Edinburgh's Neil Henderson isolated hepatic non-parenchymal cells for single-cell RNA sequencing. As they reported today in Nature, they molecularly characterized cell types present in cirrhotic and healthy livers and found a number of pro-fibrogenic pathways that are active in scar tissue and that drugs could potentially target.

"Our work illustrates the power of single-cell transcriptomics to decode the cellular and molecular basis of human organ fibrosis, providing a conceptual framework for the discovery of relevant therapeutic targets to treat patients with a broad range of fibrotic diseases," the researchers wrote in their paper.

Henderson and his colleagues isolated cells from healthy and cirrhotic liver tissue and FACS-sorted them into leucocytes, which are CD45+ cells, and other non-parenchymal cell lineages. Once sorted, they conducted single-cell RNA sequencing and clustered these 66,135 cells, from five healthy and five cirrhotic human livers, into 21 different populations.

Using the expression of marker gene signatures as a guide, they inferred the cell lineages for each of the cells, marking them as, for instance, mesenchymal or mast cells.

As previous studies in rodents have suggested a role for macrophage subpopulations in liver fibrosis progression and regression, the researchers particularly focused on their set of 10,737 mononuclear phagocytes. Within these cells, they identified 10 clusters, some of which were more prevalent in cirrhotic versus healthy liver tissue. For instance, two scar-associated macrophage (SAMΦ) subpopulations, dubbed SAMΦ(1) and SAMΦ(2), were both expanded in cirrhotic tissue and expressed the unique markers TREM2 and CD9. They further exhibited a hybrid phenotype that blended features of tissue monocytes and Kupffer cells, and further promoted fibrillar collagen expression, suggesting the SAMΦ subpopulations have pro-fibrogenic phenotypes.

The researchers also homed in on gene expression signatures that defined the SAMΦ cells, finding that these signatures include genes like TREM2, IL1B, and CCR2, which are all involved in regulating scar-producing myofibroblasts. An in silico trajectory analysis of SAMΦ suggested that these cells are derived from monocytes and are a terminally differentiated cell state that's found within the fibrotic niche.

The researchers uncovered three gene co-expression modules that are expressed as monocytes differentiate. One of these, module 1, harbored pro-fibrogenic genes, and its expression is increased along the SAMΦ path.

In a cohort of patients with non-alcoholic fatty liver disease, the researchers found SAMΦ expansion among patients with non-alcoholic steatohepatitis (NASH) and increased SAMΦ frequency with worsening NASH and increasing fibrosis. These findings, they said, suggest TREM2+ CD9+ SAMΦ are derived from circulating monocytes, have a fibrogenic phenotype, and are involved in early disease progression.

The researchers likewise uncovered seven subpopulations of hepatic endothelial cells, two of which, called SAEndo(1) and SAEndo(2), were disease specific, expanded in cirrhotic liver tissue, and only present in the fibrotic niche. Similarly, they teased out four different populations of liver mesenchynal cells, including one expressing PDGFRA that was expanded in cirrhotic livers and expressed high levels of pro-fibrogenic genes, which they dubbed SAMes.

These three scar-associated cell populations interacted, affecting the activity of pro-fibrogenic pathways, including the TNFRSF12A, PDGFR, and NOTCH signaling pathways

Drugs could potentially target these pathways, the researchers wrote, noting that there are currently no effective antifibrotic therapies for liver cirrhosis.

In a separate study, also appearing today in Nature, researchers from Newcastle University generated a different single-cell liver transcriptome atlas. Theirs focused on how the blood and immune system develop in fetuses. They reported that the fetal liver generates 'mother' hematopoietic stem cells that remain in the liver, but the resulting 'daughter' or progenitor cells travel to other tissues where they then mature into red blood cells. This finding, the researchers noted in a statement, could have implications for regenerative medicine.