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Liver Sinusoidal Endothelial Cells

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ABSTRACT

The liver sinusoidal endothelial cell (LSEC) forms the fenestrated wall of the hepatic sinusoid and functions as a control post regulating and surveying the trafficking of molecules and cells between the liver parenchyma and the blood. The cell acts as a scavenger cell responsible for removal of potential dangerous macromolecules from blood, and is increasingly acknowledged as an important player in liver immunity. This review provides an update of the major functions of the LSEC, including its role in plasma ultrafiltration and regulation of the hepatic microcirculation, scavenger functions, immune functions, and role in liver aging, as well as issues that are either undercommunicated or confusingly dealt with in the literature. These include metabolic functions, including energy metabolic interplay between the LSEC and the hepatocyte, and adequate ways of identifying and distinguishing the cells. © 2015 American Physiological Society. Compr Physiol 5:1751‐1774, 2015.

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Figure 1. Figure 1. Rat liver lobule. Scanning electron micrograph of the lobule structure of rat liver. Numerous sinusoids (arrow heads) are seen connecting portal venules (PV) with central venules (CV), with the liver parenchyma surrounding the sinusoids. Blood flows from the portal venule to the central venule through the sinusoids. Scale bar: 50 μm.
Figure 2. Figure 2. The liver sinusoid, with its main cell types. Cartoon of the liver sinusoid, illustrating the localization of hepatocytes (HC), liver sinusoidal endothelial cells (LSEC), liver resident macrophages or Kupffer cells (KC), and stellate cells (SC). The stellate cells are located in the perisinusoidal space of Disse, whereas Kupffer cells are normally located at the luminal side of the endothelial lining. For simplicity the sparse connective tissue underlying the LSECs has not been included in the cartoon. RBC, red blood cell; WBC, white blood cell. Blue and green dots represent soluble macromolecules.
Figure 3. Figure 3. Morphology of the liver sinusoidal endothelial cell. (A) Transmission electron micrograph of a transversally cut rat liver sinusoid. The very thin attenuated cytoplasm of the liver sinusoidal endothelial cell (LSEC) contains numerous fenestrations (arrow heads). Part of a stellate cell (SC), as well as microvilli of the surrounding hepatocytes (HC) can be seen in the perisinusoidal space of Disse. (B, C) Coated pits (arrows) are visible on the luminal and abluminal sides of an LSEC. LSEC fenestrae (arrow heads) can be observed. Note the scarcity of connective tissue structures along the abluminal aspect of the LSECs, demonstrating that the fenestrae provide open channels allowing bidirectional traffic of fluids, solutes, and small particles between the blood and liver parenchyma. (D, E) Scanning electron micrograph of mouse liver showing numerous fenestrae and high porosity of LSECs (overview in D; close‐up in E). The fenestrae are mostly located in sieve plates (encircled in E). HC, hepatocyte; SD, space of Disse. (F, G) Scanning electron micrographs of rat LSECs in culture. Freshly isolated LSECs were plated on collagen coated tissue culture plastic and fixed 2 h after seeding. The cells are highly fenestrated. N, nucleus. (G) High magnification showing details of LSEC fenestration. The fenestrae are mostly organized in sieve plates (encircled), but mesh‐like structures (arrow heads) and single holes can also be seen.
Figure 4. Figure 4. Fate of extracellular matrix turnover products, and the role of liver scavenger cells in their clearance. Extracellular matrix in all parts of the body is continuously being produced and degraded. (A) The turnover of the extracellular matrix takes place by initial enzymatic release of large molecular fragments. (B) Some of these large degradation products may be endocytosed and digested locally by macrophages and other connective tissue cells, but (C) a large proportion is transported with lymph to lymph nodes where uptake and degradation take place in macrophages and endothelial cells (). (D) The fragments that escape uptake in lymph node cells find their way to the circulation (), from where they are cleared by endocytosis in liver scavenger cells. The liver sinusoidal endothelial cells (LSECs) are the major site of uptake of a range of soluble macromolecular fragments, whereas particulate material is phagocytosed by the Kupffer cells ().
Figure 5. Figure 5.

The LSECs are highly effective scavenger cells. The LSECs have a much higher endocytic activity than other vascular endothelia, and effectively clear the blood of a multitude of soluble macromolecules and colloidal ligands [() Table )]. The rapid clearance kinetics of blood‐borne macromolecules taken up in LSECs is exemplified in A‐C by the fate of 125I‐labeled formaldehyde‐treated serum albumin (FSA) after tail vein injection in mouse (dose: 25 μg 125I‐FSA/kg body weight) [data reproduced from () with permission].

125I‐FSA has been previously shown to distribute mainly to LSECs after intravenous injection (). (A) Pharmacokinetics of 125I‐FSA, with extremely short circulatory survival of ligand. (B) Kinetics of release of 125I‐labeled degradation product to the blood, starting 10 min after the administration of 125I‐FSA, reflecting rapid intralysosomal degradation. (C) Organ distribution of 125I‐FSA after 10 min. (D‐F) Fluorescence microscopy images of a mouse liver section showing colocalization of endocytosed fluorescein isothiocyanate labeled FSA (FITC‐FSA; green fluorescence in D) with the staining pattern of anti mannose receptor antibodies (red fluorescence in E), a specific LSEC marker (). Overlay of red and green fluorescence are shown as orange/yellow in F. The anesthetized mouse was sacrificed 10 min after tail vein injection of FITC‐FSA (dose 2 mg/kg body weight), then perfusion fixed, and tissues processed for paraffin sectioning and immune staining. The original experiment is described in ().

Figure 6. Figure 6. Metabolic interplay between LSECs and hepatocytes. Various macromolecules and nanocompounds are taken up from the blood by receptor‐mediated endocytosis (), and metabolized through the endo‐lysosomal pathway (). Acid hydrolases degrade endocytosed macromolecules to basic metabolic building blocks, for example, monosaccharides and amino acids. Some of these are degraded further in the LSEC cytoplasm to lactate and acetate that are transferred to the hepatocyte () and used in mitochondrial reactions largely to produce energy (). Glutamate is included in step () to indicate that it may enter the Krebs cycle in mitochondria of hepatocytes. The distinct roles of LSECs and hepatocytes in hepatic glutamine homeostasis are indicated by the lysosomal location of kidney type (k‐) glutaminase in LSECs, as compared with the mitochondrial location of the liver type (h‐) glutaminase in the hepatocytes. Following transport of glutamine to the lysosome of the LSEC () or its generation from lysosomal hydrolysis of proteins in same cell type (), ammonium (NH3) generated by the action of k‐type glutaminase is transferred to mitochondria of hepatocytes, where it is incorporated in urea and excreted. Glutamine transported into hepatocytes () is hydrolyzed by h‐type glutaminase in the mitochondria to NH3, which enters the urea cycle to be incorporated in urea. See section on LSEC metabolism for more details.
Figure 7. Figure 7. Response of LSECs to toxicants. Scanning electron micrographs illustrating the morphological response of the hepatic sinusoids of C57/BL6 mice 6 h after oral acetaminophen administration (dose: 600 mg/kg in water). The animal experimental protocol is described in (). (A) Normal liver from control animal—note numerous fenestrae organized in sieve plates and the absence of gaps in LSECs. SD, space of Disse; HC, hepatocytes. Images in B, C, and D show liver tissue 6 h after oral acetaminophen administration—note the loss of fenestrations and the enlargement of the space of Disse (SD), gap formations in LSEC (arrows), and the penetration of red blood cells (RBC) into the space of Disse. Image 7D is reproduced from () with permission.


Figure 1. Rat liver lobule. Scanning electron micrograph of the lobule structure of rat liver. Numerous sinusoids (arrow heads) are seen connecting portal venules (PV) with central venules (CV), with the liver parenchyma surrounding the sinusoids. Blood flows from the portal venule to the central venule through the sinusoids. Scale bar: 50 μm.


Figure 2. The liver sinusoid, with its main cell types. Cartoon of the liver sinusoid, illustrating the localization of hepatocytes (HC), liver sinusoidal endothelial cells (LSEC), liver resident macrophages or Kupffer cells (KC), and stellate cells (SC). The stellate cells are located in the perisinusoidal space of Disse, whereas Kupffer cells are normally located at the luminal side of the endothelial lining. For simplicity the sparse connective tissue underlying the LSECs has not been included in the cartoon. RBC, red blood cell; WBC, white blood cell. Blue and green dots represent soluble macromolecules.


Figure 3. Morphology of the liver sinusoidal endothelial cell. (A) Transmission electron micrograph of a transversally cut rat liver sinusoid. The very thin attenuated cytoplasm of the liver sinusoidal endothelial cell (LSEC) contains numerous fenestrations (arrow heads). Part of a stellate cell (SC), as well as microvilli of the surrounding hepatocytes (HC) can be seen in the perisinusoidal space of Disse. (B, C) Coated pits (arrows) are visible on the luminal and abluminal sides of an LSEC. LSEC fenestrae (arrow heads) can be observed. Note the scarcity of connective tissue structures along the abluminal aspect of the LSECs, demonstrating that the fenestrae provide open channels allowing bidirectional traffic of fluids, solutes, and small particles between the blood and liver parenchyma. (D, E) Scanning electron micrograph of mouse liver showing numerous fenestrae and high porosity of LSECs (overview in D; close‐up in E). The fenestrae are mostly located in sieve plates (encircled in E). HC, hepatocyte; SD, space of Disse. (F, G) Scanning electron micrographs of rat LSECs in culture. Freshly isolated LSECs were plated on collagen coated tissue culture plastic and fixed 2 h after seeding. The cells are highly fenestrated. N, nucleus. (G) High magnification showing details of LSEC fenestration. The fenestrae are mostly organized in sieve plates (encircled), but mesh‐like structures (arrow heads) and single holes can also be seen.


Figure 4. Fate of extracellular matrix turnover products, and the role of liver scavenger cells in their clearance. Extracellular matrix in all parts of the body is continuously being produced and degraded. (A) The turnover of the extracellular matrix takes place by initial enzymatic release of large molecular fragments. (B) Some of these large degradation products may be endocytosed and digested locally by macrophages and other connective tissue cells, but (C) a large proportion is transported with lymph to lymph nodes where uptake and degradation take place in macrophages and endothelial cells (). (D) The fragments that escape uptake in lymph node cells find their way to the circulation (), from where they are cleared by endocytosis in liver scavenger cells. The liver sinusoidal endothelial cells (LSECs) are the major site of uptake of a range of soluble macromolecular fragments, whereas particulate material is phagocytosed by the Kupffer cells ().


Figure 5.

The LSECs are highly effective scavenger cells. The LSECs have a much higher endocytic activity than other vascular endothelia, and effectively clear the blood of a multitude of soluble macromolecules and colloidal ligands [() Table )]. The rapid clearance kinetics of blood‐borne macromolecules taken up in LSECs is exemplified in A‐C by the fate of 125I‐labeled formaldehyde‐treated serum albumin (FSA) after tail vein injection in mouse (dose: 25 μg 125I‐FSA/kg body weight) [data reproduced from () with permission].

125I‐FSA has been previously shown to distribute mainly to LSECs after intravenous injection (). (A) Pharmacokinetics of 125I‐FSA, with extremely short circulatory survival of ligand. (B) Kinetics of release of 125I‐labeled degradation product to the blood, starting 10 min after the administration of 125I‐FSA, reflecting rapid intralysosomal degradation. (C) Organ distribution of 125I‐FSA after 10 min. (D‐F) Fluorescence microscopy images of a mouse liver section showing colocalization of endocytosed fluorescein isothiocyanate labeled FSA (FITC‐FSA; green fluorescence in D) with the staining pattern of anti mannose receptor antibodies (red fluorescence in E), a specific LSEC marker (). Overlay of red and green fluorescence are shown as orange/yellow in F. The anesthetized mouse was sacrificed 10 min after tail vein injection of FITC‐FSA (dose 2 mg/kg body weight), then perfusion fixed, and tissues processed for paraffin sectioning and immune staining. The original experiment is described in ().



Figure 6. Metabolic interplay between LSECs and hepatocytes. Various macromolecules and nanocompounds are taken up from the blood by receptor‐mediated endocytosis (), and metabolized through the endo‐lysosomal pathway (). Acid hydrolases degrade endocytosed macromolecules to basic metabolic building blocks, for example, monosaccharides and amino acids. Some of these are degraded further in the LSEC cytoplasm to lactate and acetate that are transferred to the hepatocyte () and used in mitochondrial reactions largely to produce energy (). Glutamate is included in step () to indicate that it may enter the Krebs cycle in mitochondria of hepatocytes. The distinct roles of LSECs and hepatocytes in hepatic glutamine homeostasis are indicated by the lysosomal location of kidney type (k‐) glutaminase in LSECs, as compared with the mitochondrial location of the liver type (h‐) glutaminase in the hepatocytes. Following transport of glutamine to the lysosome of the LSEC () or its generation from lysosomal hydrolysis of proteins in same cell type (), ammonium (NH3) generated by the action of k‐type glutaminase is transferred to mitochondria of hepatocytes, where it is incorporated in urea and excreted. Glutamine transported into hepatocytes () is hydrolyzed by h‐type glutaminase in the mitochondria to NH3, which enters the urea cycle to be incorporated in urea. See section on LSEC metabolism for more details.


Figure 7. Response of LSECs to toxicants. Scanning electron micrographs illustrating the morphological response of the hepatic sinusoids of C57/BL6 mice 6 h after oral acetaminophen administration (dose: 600 mg/kg in water). The animal experimental protocol is described in (). (A) Normal liver from control animal—note numerous fenestrae organized in sieve plates and the absence of gaps in LSECs. SD, space of Disse; HC, hepatocytes. Images in B, C, and D show liver tissue 6 h after oral acetaminophen administration—note the loss of fenestrations and the enlargement of the space of Disse (SD), gap formations in LSEC (arrows), and the penetration of red blood cells (RBC) into the space of Disse. Image 7D is reproduced from () with permission.
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Video 1 Sinusoidal blood flow in mouse liver—normal flow, and reduced flow after lipopolysaccharide treatment. This video clip shows healthy hepatic microcirculation with flat liver sinusoidal endothelial cells (LSEC; – points to the nuclear region of a normal LSEC) and good blood flow, no formed elements sticking to the endothelium or to each other. The second video clip shows a swollen LSEC (– points to the nuclear region of a swollen LSEC), and reduced irregular blood flow in the sinusoids during hepatic microvascular inflammatory response to low dose of bacterial lipopolysaccharide (LPS; intravenous administration; 0.4 μg per 25 g mouse). The livers of anesthetized mice were studied by in vivo microscopy as reported in (63, 105-108, 161, 164, 162, 165, 166, 186). Sinusoidal blood flow in liver is reviewed in (164). See Video 1 at http://www.comprehensivephysiology.com/WileyCDA/CompPhysArticle/refId-c140078.html.

Video 2 Sinusoidal blood flow in mouse liver—enhanced hepatic microvascular inflammatory response to ethanol and lipopolysaccharide. Impairment of sinusoidal blood flow by white blood cells (WBC) plugging behind swollen liver sinusoidal endothelial cell (LSEC) during enhanced hepatic microvascular inflammatory response to ethanol and treatment with low dose bacterial lipopolysaccharide (LPS). Swollen LSEC with WBC plug are indicated by –. A totally plugged sinusoid is also indicated. Relevant experiments are described in (63, 186). Sinusoidal blood flow in liver is reviewed in (164). The motion artifact is caused by respiratory movements. See Video 2 at http://www.comprehensivephysiology.com/WileyCDA/CompPhysArticle/refId-c140078.html.




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Karen Kristine Sørensen, Jaione Simon‐Santamaria, Robert S. McCuskey, Bård Smedsrød. Liver Sinusoidal Endothelial Cells. Compr Physiol 2015, 5: 1751-1774. doi: 10.1002/cphy.c140078