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. Words: 169

The Role of Sinusoidal Endothelial Cells in the Axis of Inflammation and Cancer Within the Liver

“…Whilst it has an instrumental role in foetal liver-derived immune cell distribution ( Rantakari et al, 2016 ), its involvement in leukocyte recruitment within adult liver remains to be explored. Nevertheless, PLVAP seems to be upregulated during inflammatory states ( Ramachandran et al, 2019 ; Su et al, 2020 ), and its re-emergence in the HCC microenvironment ( Wang et al, 2014 ) suggests a role in pathogenesis which requires further investigation.…”

Adipocyte Fatty Acid Binding Protein Promotes the Onset and Progression of Liver Fibrosis via Mediating the Crosstalk between Liver Sinusoidal Endothelial Cells and Hepatic Stellate Cells

“…[ 38 ] By using single‐cell transcriptomics, Zone 3 LSECs in cirrhotic mouse liver was found to be most susceptible to capillarization as CD34, a marker of LSEC capillarization, and the genes of extracellular matrix were most upregulated in Zone 3 LSECs among the three clusters of LSECs in Zones 1, 2, and 3. [ 39 ] In the present study, LSECs (stabilin‐2 + /CD11b − ) were sorted and used in the in vitro system. As more than 95% stabilin‐2 + LSECs were reported to be LYVE‐1 positive, [ 17 ] thus the LSECs used in our in vitro studies are mainly type 2 LSECs, which include the Zone 3 LSECs with large fenestrae and exhibited the highest potential to capillarization.…”

Phosphodiesterases in the Liver as Potential Therapeutic Targets of Cirrhotic Portal Hypertension

“…Liver cirrhosis is associated with loss of metabolic zonation due to structural modifications of the liver architecture and altered expression of many genes. The latter has extensively been investigated in the recent years using single cell RNA expressing techniques, both in hepatocytes and in non-parenchymal cells [ 110 , 111 , 112 , 113 , 114 , 115 ]. Alterations in expression, activity, and distribution of key enzymes and molecules, which are involved in the NO-cGMP pathway, as well as their specific role in PH pathophysiology have not been investigated in these studies.…”

“…Alterations in expression, activity, and distribution of key enzymes and molecules, which are involved in the NO-cGMP pathway, as well as their specific role in PH pathophysiology have not been investigated in these studies. Recently, Su et al [ 110 ] detected a disrupted zonation and increased expression of endothelin-receptor-B (ET-B) receptor in liver sinusoidal cells using single-cells transcriptomics. Reduced NO availability and increased constrictive response to endothelin-1 in liver cirrhosis could be a consequence of ET-B receptor disturbance.…”

“…Angiotensin II is generated via angiotensin converting enzyme (ACE) and is a peripheral vasoconstrictor. It is further degraded by ACE2 to the vasodilating peptide Ang (1–7), which binds to the G-protein coupled receptor Mas and leads to eNOS activation and consecutively to excess NO production [ 19 , 110 , 132 , 133 ].…”