Paired-cell sequencing enables spatial gene expression mapping of liver endothelial cells

Wnt target genes and key metabolic enzymes have a zonated expression pattern in pericentral hepatocytes.

“creating a zonated expression pattern of Wnt target genes and key metabolic enzymes in pericentral hepatocytes (20–22).”

Pericentral ECs constitute a second liver cell population with high expression of Rspo3.

“In addition to HSCs, pericentral ECs constitute a second liver cell population with high expression of Rspo331,40,41, confirmed by scRNA-seq and snRNA-seq, ELISA, immunoblotting and spatial transcriptomics (Fig. 3c,e,j and Extended Data Fig. 6a–c,i).”

No clear patterns of zonation in gene expression within non-parenchymal populations were noted, suggesting that if such gradients exist in the human liver, the MERFISH library does not contain the proper genes to capture them.

“We did not note clear patterns of zonation in gene expression within these non-parenchymal populations28–30, suggesting that, if such gradients exist in the human liver, our MERFISH library does not contain the proper genes to capture them.”

Murine liver injury-associated macrophages show significant overlap of marker genes with human scar-associated macrophages, with TREM2 and CD9 conserved across species.

“Of note, murine liver injury-associated macrophages show significant overlap of marker genes with those observed for human scar-associated macrophages, with TREM2 and CD9 demonstrating conservation across species18.”

Disease-associated ACKR1+ and PLVAP+ endothelial cell subpopulations are topographically restricted to the fibrotic niche and enhance leucocyte transmigration.

“Disease-associated atypical chemokine receptor (ACKR1)+ and plasmalemma vesicle-associated protein (PLVAP)+ endothelial cell subpopulations which are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes were also defined.”

A novel scar-associated TREM2+CD9+ macrophage subpopulation expands in liver fibrosis, differentiates from circulating monocytes, and is pro-fibrogenic.

“allowing identification of a novel scar-associated triggering receptor expressed on a myeloid cell (TREM)2+CD9+ subpopulation of macrophages which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic18.”

Several recent studies have identified subpopulations of monocytes and macrophages that can regulate fibrosis and tissue remodelling.

“Several recent studies have identified subpopulations of monocytes and macrophages which have the capacity to regulate fibrosis and tissue remodelling18,61,68–71.”

Pro-fibrotic macrophages commonly coordinate scar formation via interactions with fibroblasts, the major cellular source of pathological extracellular matrix deposition during fibrosis.

“pro-fibrotic macrophages commonly coordinate scar formation via a range of interactions with fibroblasts, the major cellular source of pathological extracellular matrix deposition during fibrosis18,27,74–78.”