Single-cell transcriptomics reveals zone-specific alterations of liver sinusoidal endothelial cells in cirrhosis

Abstract

Dysfunction of liver endothelial cells (ECs), particularly sinusoidal endothelial cells (LSECs), is permissive for the progression of liver fibrosis/cirrhosis and responsible for its clinical complications. Here, we have mapped the spatial distribution of heterogeneous liver ECs in normal versus cirrhotic mouse livers and identified zone-specific transcriptomic changes of LSECs associated with liver cirrhosis using single-cell RNA sequencing technology. We identified 6 clusters of liver EC populations including 3 clusters of LSECs, 2 clusters of vascular ECs and 1 cluster of lymphatic ECs. To add finer detail, we mapped the 3 clusters of LSECs to Zones 1 to 3. We found that heterogeneous liver EC identities are conserved even in liver cirrhosis and that Zone 3 LSECs are most susceptible to damage associated with liver cirrhosis, demonstrating increased capillarization and decreased ability to regulate endocytosis. Altogether, this study deepens our knowledge of the pathogenesis of liver cirrhosis at a spatial, cell-specific level, which is indispensable for the development of novel therapeutic strategies to target the most highly dysfunctional liver ECs.