Role of liver sinusoidal endothelial cells in liver diseases

Liver sinusoidal endothelial cells (LSECs) form the wall of the hepatic sinusoids. Unlike other capillaries, they lack an organized basement membrane and have cytoplasm that is penetrated by open fenestrae, making the hepatic microvascular endothelium discontinuous. LSECs have essential roles in the maintenance of hepatic homeostasis, including regulation of the vascular tone, inflammation and thrombosis, and they are essential for control of the hepatic immune response. On a background of acute or chronic liver injury, LSECs modify their phenotype and negatively affect neighbouring cells and liver disease pathophysiology. This Review describes the main functions and phenotypic dysregulations of LSECs in liver diseases, specifically in the context of acute injury (ischaemia–reperfusion injury, drug-induced liver injury and bacterial and viral infection), chronic liver disease (metabolism-associated liver disease, alcoholic steatohepatitis and chronic hepatotoxic injury) and hepatocellular carcinoma, and provides a comprehensive update of the role of LSECs as therapeutic targets for liver disease. Finally, we discuss the open questions in the field of LSEC pathobiology and future avenues of research. Liver sinusoidal endothelial cells (LSECs) form the wall of the hepatic sinusoids and have essential roles in hepatic homeostasis. This Review describes the phenotypic dysregulations of LSECs in the context of liver disease and hepatocellular carcinoma, and provides an update of the role of LSECs as therapeutic targets. Key points Liver sinusoidal endothelial cells (LSECs) form the vascular wall of the hepatic microcirculatory system, the hepatic sinusoid, and exhibit unique phenotypic characteristics, including open fenestrae and lack of a basement membrane. In health, LSECs have key roles maintaining hepatic homeostasis and are critical for several processes, including immune regulation, control of inflammation, modulation of vascular tone and regulation of the coagulation cascade. LSECs become rapidly dedifferentiated during acute and chronic liver injuries, acquiring vasoconstrictor, proinflammatory and prothrombotic properties; this process, termed ‘capillarization’, contributes to the activation and dedifferentiation of other hepatic cells. LSEC capillarization plays a key part in the pathophysiology of major liver diseases, including ischaemia–reperfusion injury, drug-induced liver injury, chronic liver disease and hepatocellular carcinoma; several LSEC