The liver sinusoidal endothelial cell: a cell type of controversial and confusing identity

Elvevold, Kjetil; Smedsrød, Bård; Martínez, Iñigo

doi:10.1152/ajpgi.00167.2007

Cited by 213 publications

(222 citation statements)

References 82 publications

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“…LSECs are also functionally unique. The high activity of receptor-mediated endocytosis provides LSECs with a high-rate, high-capacity system to clear colloids and soluble waste macromolecules from the circulation (11,12). The three main receptors for endocytosis are the mannose receptor, the scavenger receptor, and the Fcγ receptor IIb2 (12).…”

Section: Lsecs and Their Progenitorsmentioning

confidence: 99%

Liver sinusoidal endothelial cells and liver regeneration

2013

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Liver sinusoidal endothelial cells (LSECs) have long been noted to contribute to liver regeneration after liver injury. In normal liver, the major cellular source of HGF is the hepatic stellate cell, but after liver injury, HGF expression has been thought to increase markedly in proliferating LSECs. However, emerging data suggest that even after injury, LSEC expression of HGF does not increase greatly. In contrast, bone marrow progenitor cells of LSECs (BM SPCs), which are rich in HGF, are recruited to the liver after injury. This Review examines liver regeneration from the perspective that BM SPCs that have been recruited to the liver, rather than mature LSECs, drive liver regeneration.

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Section: Lsecs and Their Progenitorsmentioning

confidence: 99%

Liver sinusoidal endothelial cells and liver regeneration

2013

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“…The SEC architecture, including open fenestrations and weak junctional association between cells, provides a dynamic filtration system with low perfusion pressure that enables nutrients and macromolecular waste to pass freely to hepatocytes for efficient metabolism. The highly active, clathrinmediated scavenging system in the SEC contributes significantly to endocytic clearance of waste from blood, including effective removal of pathogenic acylated or glycosylated proteins (10,11). In addition, the SECs are antigen-presenting cells, and interactions with SECs and underlying hepatocyte microvilli may be important for naive T cell activation (12).…”

Section: Introductionmentioning

confidence: 99%

Arsenic-stimulated liver sinusoidal capillarization in mice requires NADPH oxidase–generated superoxide

Straub

Clark²,

Ross³

et al. 2008

J. Clin. Invest.

105

114

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Environmental arsenic exposure, through drinking contaminated water, is a significant risk factor for developing vascular diseases and is associated with liver portal hypertension, vascular shunting, and portal fibrosis through unknown mechanisms. We found that the addition of low doses of arsenite to the drinking water of mice resulted in marked pathologic remodeling in liver sinusoidal endothelial cells (SECs), including SEC defenestration, capillarization, increased junctional PECAM-1 expression, protein nitration, and decreased liver clearance of modified albumin. Furthermore, the pathologic changes observed after in vivo exposure were recapitulated in isolated mouse SECs exposed to arsenic in culture. To investigate the role of NADPH oxidase-generated ROS in this remodeling, we examined the effect of arsenite in the drinking water of mice deficient for the p47 subunit of the NADPH oxidase and found that knockout mice were protected from arsenite-induced capillarization and protein nitration. Furthermore, ex vivo arsenic exposure increased SEC superoxide generation, and this effect was inhibited by addition of a Nox2 inhibitor and quenched by the cellpermeant superoxide scavenger. In addition, inhibiting either oxidant generation or Rac1-GTPase blocked ex vivo arsenic-stimulated SEC differentiation and dysfunction. Our data indicate that a Nox2-based oxidase is required for SEC capillarization and that it may play a central role in vessel remodeling following environmentally relevant arsenic exposures.

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“…37 Despite these advances in culture of LSECs alone, or with hepatocytes, their long-term culture and viability is still poorly understood. 44,45 While several strategies for LSEC culture have been proposed, 15,39,46 longterm maintenance of LSECs remains challenging.…”

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confidence: 99%

Long-Term Coculture Strategies for Primary Hepatocytes and Liver Sinusoidal Endothelial Cells

Bale

Golberg

Jindal

et al. 2015

Tissue Engineering Part C: Methods

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Hepatocytes and their in vitro models are essential tools for preclinical screening studies for drugs that affect the liver. Most of the current models primarily focus on hepatocytes alone and lack the contribution of nonparenchymal cells (NPCs), which are significant through both molecular and the response of the NPCs themselves. Models that incorporate NPCs alongside hepatocytes hold the power to enable more realistic recapitulation and elucidation of cell interactions and cumulative drug response. Hepatocytes and liver sinusoidal endothelial cells (LSECs) account for *80% of the liver mass where the LSECs line the walls of blood vessels, and act as a barrier between hepatocytes and blood. Culturing LSECs with hepatocytes to generate multicellular physiologically relevant in vitro liver models has been a major hurdle since LSECs lose their phenotype rapidly after isolation. To this end, we describe the application of collagen gel (1) in a sandwich and (2) as an intervening extracellular matrix layer to coculture hepatocytes with LSECs for extended periods. These coculture configurations provide environments wherein hepatocyte and LSECs, through cell-cell contacts and/or secretion factors, lead to enhanced function and stability of the cocultures. Our results show that in these configurations, hepatocytes and LSECs maintained their phenotypes when cultured together as a mixture, and showed stable secretion and metabolic activity for up to 4 weeks. Immunostaining for sinusoidal endothelial 1 (SE-1) antibody demonstrated retention of LSEC phenotype during the culture period. In addition, LSECs cultured alone maintained high viability and SE-1 expression when cultured within a collagen sandwich configuration up to 4 weeks. Albumin production of the cocultures was 10-15 times higher when LSECs were cultured as a bottom layer (with an intervening collagen layer) and as a mixture in a sandwich configuration, and native CYP 1A1/2 activity was at least 20 times higher than monoculture controls. Together, these data suggest that collagen gel-based hepatocyte-LSEC cocultures are highly suitable models for stabilization and long-term culture of both cell types. In summary, these results indicate that collagen gel-based hepatocyte-LSEC coculture models are promising for in vitro toxicity testing, and liver model development studies.

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The liver sinusoidal endothelial cell: a cell type of controversial and confusing identity

Cited by 213 publications

References 82 publications

Liver sinusoidal endothelial cells and liver regeneration

Liver sinusoidal endothelial cells and liver regeneration

Arsenic-stimulated liver sinusoidal capillarization in mice requires NADPH oxidase–generated superoxide

Long-Term Coculture Strategies for Primary Hepatocytes and Liver Sinusoidal Endothelial Cells

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