Chemokines and adhesion molecules expressed by inflamed LSECs are also potential targets for anti-inflammatory therapy in liver disease. usually refer to them as liver sinusoidal endothelial cells (LSECs), whereas isolated human cells have also been referred to as human hepatic sinusoidal endothelial cells (HSECs). For the purpose of this Review, we use the term LSEC. The exposure of these sinusoidal endothelial cells to blood originating from both the gut and the systemic circulation means they are ideally situated to remove and recycle blood-borne proteins and lipids. In combination with Kupffer cells (KCs; liver-resident macrophages), LSECs constitute the most powerful scavenger system in the body1. This activity is facilitated by the presence of fenestrae in LSECs, their lack of a AMG 837 classical basement membrane and their expression of promiscuous scavenger receptors combined with the most potent endocytic capacity in the body2. Thus, virus particles3, advanced glycation end products4 and modified LDL cholesterol5 can be cleared from the circulation within minutes by this route. Open in a separate window Fig. 1 Microanatomy of the human liver vascular tree.a | Low-power image of human liver tissue (stained with haematoxylin and eosin) illustrating the lobular organization of the liver, with zonal architecture indicated relative to the position of the portal tract. b | Expanded periportal section of the same image to illustrate the different vascular compartments within the parenchyma. c | Immunohistochemical staining of stabilin 1, which highlights liver endothelial cell distribution within hepatic tissue in a normal liver section. d | A comparison of the structure of liver sinusoidal endothelium and glomerular endothelium. Endothelial cells in different vascular beds are generated from common early embryological precursors and have broadly similar histological appearance and functional AMG 837 roles throughout the body. However, extensive variations in phenotype and function arise as a consequence of local microenvironmental signals dependent on anatomical localization6. The vascular architecture in the human liver is acquired by 17C25 weeks of gestation, but different vessels within the liver have distinct embryonic origins. Thus, portal vessels are derived from vitelline veins, whereas sinusoids develop from capillary vessels of the septum transversum and acquire their distinctive fenestrated phenotype by week 20 of gestation7 under the control of transcription factor GATA4 (ref.8). From this point onward, sinusoidal endothelial cells remain functionally and phenotypically distinct from the other vascular endothelial cells in the liver microenvironment and assume a phenotype that has many similarities with lymphatic endothelial cells9. The unique characteristics of LSECs are presented in Box?1. Both lymphatic and sinusoidal endothelial cells have minimal basement membranes and loosely organized cell junctions10 and share a complement of receptors such as lymphatic vessel endothelial hyaluronic acid receptor (LYVE1)11, prospero homeobox protein 1 (PROX1)12, podoplanin13 and liver/lymph node-specific ICAM3-grabbing non-integrin (LSIGN; also known as CLEC4M)14. It has been shown that the phenotype of sinusoidal endothelial cells varies across the liver acinus; a study of human liver tissue published in 2017 demonstrated that zone 1 LSECs are CD36hi and LYVE1low, whereas zone 2 and zone 3 LSECs are CD36low, LYVE1hi and CD32hi (ref.15). The presence of fenestrations or membranous pores organized into sieve plates is a feature that also distinguishes LSECs from the other hepatic endothelial populations2. Fenestrations are not unique to hepatic endothelial cells and are also MYO7A found in endothelium in endocrine glands such as the pancreas16, kidney17, spleen18 and bone marrow19 and are sometimes observed in tumour vasculature20. However, unlike other fenestrated endothelial AMG 837 populations such as those in the kidney, hepatic fenestrations lack a diaphragm or basal lamina and are grouped into organized sieve plates, rendering LSECs highly permeable (Fig.?1d). Many studies have implicated vascular endothelial growth factor (VEGF) as an essential factor for regulation of fenestrations21, but dynamic changes in hepatic fenestration number and size can occur rapidly in response to agents such as alcohol22, dietary constituents23 AMG 837 and fasting24 or calorie restriction25. The fenestrations act.