Angiocrine Signaling in Sinusoidal Health and Disease

Abstract

Liver sinusoidal endothelial cells (LSECs) are key players in maintaining hepatic homeostasis. They also play crucial roles during liver injury by communicating with liver cell types as well as immune cells and promoting portal hypertension, fibrosis and inflammation. Cutting-edge technology, such as single cell and spatial transcriptomics, have revealed the existence of distinct LSEC subpopulations with a clear zonation in the liver. The signals released by LSECs are commonly called “angiocrine signaling”. In this review, we summarize the role of angiocrine signaling in health and disease, including zonation in healthy liver, regeneration, fibrosis, portal hypertension, non-alcoholic fatty liver disease, alcohol-associated liver disease, aging, drug-induced liver injury, and ischemia/reperfusion, as well as potential therapeutic advances. In conclusion, sinusoidal endotheliopathy is recognized in liver disease and promising pre-clinical studies are paving the path towards LSEC-specific pharmacotherapies.

Cold stress–induced ferroptosis in liver sinusoidal endothelial cells determines liver transplant injury and outcomes

“…Nonalcoholic fatty liver disease (NAFLD) affects LSEC phenotypes. The loss of fenestration, observed in cold-stored liver grafts by scanning electron microscopy ( Figure 2H ), can also be seen during early NAFLD development, i.e., at the steatosis stage in human livers ( 56 ). In addition, during the progression of steatohepatitis, LSECs become proinflammatory, characterized by the increase of cytokine/chemokine release and upregulation of adhesion molecules ( 56 ).…”

“…The loss of fenestration, observed in cold-stored liver grafts by scanning electron microscopy ( Figure 2H ), can also be seen during early NAFLD development, i.e., at the steatosis stage in human livers ( 56 ). In addition, during the progression of steatohepatitis, LSECs become proinflammatory, characterized by the increase of cytokine/chemokine release and upregulation of adhesion molecules ( 56 ). As microcirculatory dysfunction represents the main mechanism of IRI-triggered hepatocellular damage in steatotic livers ( 10 ), protecting LSECs during cold storage may lead to the safe usage of steatotic livers.…”