The study by Ramachandran et al. (2019) uses single-cell transcriptomics to resolve the fibrotic niche of human liver cirrhosis, aiming to identify cellular and molecular mechanisms underlying liver fibrosis and inform therapeutic development. The researchers profiled over 100,000 primary human single cells from healthy and cirrhotic livers, uncovering novel subpopulations of cells that contribute to fibrosis. Key findings include: 1. **Novel Macrophage Subpopulation**: A subpopulation of TREM2+CD9+ macrophages, which expand in human and mouse liver fibrosis, have a distinct differentiation trajectory from circulating monocytes and display a pro-fibrogenic phenotype. 2. **Endothelial Cell Subpopulations**: Two new subpopulations of ACKR1+ and PLVAP+ endothelial cells were identified, which expand in cirrhosis and enhance leucocyte transmigration in fibrotic septa. 3. **Ligand-Receptor Interactions**: Multi-lineage ligand-receptor modeling revealed intra-scar activity of several major pro-fibrogenic pathways, including TNFRSF12A, PDGFR, and NOTCH signaling. 4. **Clinical Relevance**: The study demonstrates the applicability of single-cell transcriptomics to define pathogenic mechanisms in human fibrotic disorders and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis. The research highlights the importance of understanding the cellular and molecular basis of human organ fibrosis at a single-cell level, which could inform the development of more effective antifibrotic therapies.The study by Ramachandran et al. (2019) uses single-cell transcriptomics to resolve the fibrotic niche of human liver cirrhosis, aiming to identify cellular and molecular mechanisms underlying liver fibrosis and inform therapeutic development. The researchers profiled over 100,000 primary human single cells from healthy and cirrhotic livers, uncovering novel subpopulations of cells that contribute to fibrosis. Key findings include: 1. **Novel Macrophage Subpopulation**: A subpopulation of TREM2+CD9+ macrophages, which expand in human and mouse liver fibrosis, have a distinct differentiation trajectory from circulating monocytes and display a pro-fibrogenic phenotype. 2. **Endothelial Cell Subpopulations**: Two new subpopulations of ACKR1+ and PLVAP+ endothelial cells were identified, which expand in cirrhosis and enhance leucocyte transmigration in fibrotic septa. 3. **Ligand-Receptor Interactions**: Multi-lineage ligand-receptor modeling revealed intra-scar activity of several major pro-fibrogenic pathways, including TNFRSF12A, PDGFR, and NOTCH signaling. 4. **Clinical Relevance**: The study demonstrates the applicability of single-cell transcriptomics to define pathogenic mechanisms in human fibrotic disorders and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis. The research highlights the importance of understanding the cellular and molecular basis of human organ fibrosis at a single-cell level, which could inform the development of more effective antifibrotic therapies.