scholarly journals FcγRIIB on liver sinusoidal endothelial cells is essential for antibody-induced GPVI ectodomain shedding in mice

Blood ◽  
2016 ◽  
Vol 128 (6) ◽  
pp. 862-865 ◽  
Author(s):  
David Stegner ◽  
Michael Popp ◽  
Viola Lorenz ◽  
Jacqueline K. Wax ◽  
J. Engelbert Gessner ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Sinusoidal Endothelial Cell ◽  
Liver Sinusoidal Endothelial Cell ◽  
Ectodomain Shedding ◽  
Liver Sinusoidal Endothelial Cells ◽  
Sinusoidal Endothelial Cells ◽  
Key Points

Key Points Antibody-induced shedding of platelet GPVI in vivo and the associated transient thrombocytopenia depend on liver sinusoidal endothelial cell-expressed FcγRIIB.

scholarly journals The Contribution of Liver Sinusoidal Endothelial Cells to Clearance of Therapeutic Antibody

2022 ◽  
Vol 12 ◽  
Author(s):  
Bethany H. James ◽  
Pantelitsa Papakyriacou ◽  
Matthew J. Gardener ◽  
Louise Gliddon ◽  
Christopher J. Weston ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Liver Disease ◽  
Immune Cells ◽  
High Specificity ◽  
Fc Receptor ◽  
Membrane Receptors ◽  
Pharmacokinetic Studies ◽  
Liver Sinusoidal Endothelial Cells ◽  
Sinusoidal Endothelial Cells

Many chronic inflammatory diseases are treated by administration of “biological” therapies in terms of fully human and humanized monoclonal antibodies or Fc fusion proteins. These tools have widespread efficacy and are favored because they generally exhibit high specificity for target with a low toxicity. However, the design of clinically applicable humanized antibodies is complicated by the need to circumvent normal antibody clearance mechanisms to maintain therapeutic dosing, whilst avoiding development of off target antibody dependent cellular toxicity. Classically, professional phagocytic immune cells are responsible for scavenging and clearance of antibody via interactions with the Fc portion. Immune cells such as macrophages, monocytes, and neutrophils express Fc receptor subsets, such as the FcγR that can then clear immune complexes. Another, the neonatal Fc receptor (FcRn) is key to clearance of IgG in vivo and serum half-life of antibody is explicitly linked to function of this receptor. The liver is a site of significant expression of FcRn and indeed several hepatic cell populations including Kupffer cells and liver sinusoidal endothelial cells (LSEC), play key roles in antibody clearance. This combined with the fact that the liver is a highly perfused organ with a relatively permissive microcirculation means that hepatic binding of antibody has a significant effect on pharmacokinetics of clearance. Liver disease can alter systemic distribution or pharmacokinetics of antibody-based therapies and impact on clinical effectiveness, however, few studies document the changes in key membrane receptors involved in antibody clearance across the spectrum of liver disease. Similarly, the individual contribution of LSEC scavenger receptors to antibody clearance in a healthy or chronically diseased organ is not well characterized. This is an important omission since pharmacokinetic studies of antibody distribution are often based on studies in healthy individuals and thus may not reflect the picture in an aging or chronically diseased population. Therefore, in this review we consider the expression and function of key antibody-binding receptors on LSEC, and the features of therapeutic antibodies which may accentuate clearance by the liver. We then discuss the implications of this for the design and utility of monoclonal antibody-based therapies.

scholarly journals Unraveling the transcriptional determinants of liver sinusoidal endothelial cell specialization

2020 ◽  
Vol 318 (4) ◽  
pp. G803-G815
Author(s):  
Willeke de Haan ◽  
Cristina Øie ◽  
Mohammed Benkheil ◽  
Wouter Dheedene ◽  
Stefan Vinckier ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Transcription Factors ◽  
Family Member ◽  
Binding Protein ◽  
Organic Anion ◽  
Transcriptional Regulators ◽  
Liver Cells ◽  
Liver Sinusoidal Endothelial Cell ◽  
Liver Sinusoidal Endothelial Cells ◽  
Sinusoidal Endothelial Cells

Liver sinusoidal endothelial cells (LSECs) are the first liver cells to encounter waste macromolecules, pathogens, and toxins in blood. LSECs are highly specialized to mediate the clearance of these substances via endocytic scavenger receptors and are equipped with fenestrae that mediate the passage of macromolecules toward hepatocytes. Although some transcription factors (TFs) are known to play a role in LSEC specialization, information about the specialized LSEC signature and its transcriptional determinants remains incomplete. Based on a comparison of liver, heart, and brain endothelial cells (ECs), we established a 30-gene LSEC signature comprising both established and newly identified markers, including 7 genes encoding TFs. To evaluate the LSEC TF regulatory network, we artificially increased the expression of the 7 LSEC-specific TFs in human umbilical vein ECs. Although Zinc finger E-box-binding protein 2, homeobox B5, Cut-like homolog 2, and transcription factor EC (TCFEC) had limited contributions, musculoaponeurotic fibrosarcoma (C-MAF), GATA binding protein 4 (GATA4), and MEIS homeobox 2 (MEIS2) emerged as stronger inducers of LSEC marker expression. Furthermore, a combination of C-MAF, GATA4, and MEIS2 showed a synergistic effect on the increase of LSEC signature genes, including liver/lymph node-specific ICAM-3 grabbing non-integrin ( L-SIGN) (or C-type lectin domain family member M ( CLEC4M)), mannose receptor C-Type 1 ( MRC1), legumain ( LGMN), G protein-coupled receptor 182 ( GPR182), Plexin C1 ( PLXNC1), and solute carrier organic anion transporter family member 2A1 ( SLCO2A1). Accordingly, L-SIGN, MRC1, pro-LGMN, GPR182, PLXNC1, and SLCO2A1 protein levels were elevated by this combined overexpression. Although receptor-mediated endocytosis was not significantly induced by the triple TF combination, it enhanced binding to E2, the hepatitis C virus host-binding protein. We conclude that C-MAF, GATA4, and MEIS2 are important transcriptional regulators of the unique LSEC fingerprint and LSEC interaction with viruses. Additional factors are however required to fully recapitulate the molecular, morphological, and functional LSEC fingerprint. NEW & NOTEWORTHY Liver sinusoidal endothelial cells (LSECs) are the first liver cells to encounter waste macromolecules, pathogens, and toxins in the blood and are highly specialized. Although some transcription factors are known to play a role in LSEC specialization, information about the specialized LSEC signature and its transcriptional determinants remains incomplete. Here, we show that Musculoaponeurotic Fibrosarcoma (C-MAF), GATA binding protein 4 (GATA4), and Meis homeobox 2 (MEIS2) are important transcriptional regulators of the unique LSEC signature and that they affect the interaction of LSECs with viruses.

scholarly journals Kindlin-2 regulates hemostasis by controlling endothelial cell–surface expression of ADP/AMP catabolic enzymes via a clathrin-dependent mechanism

Blood ◽  
2013 ◽  
Vol 122 (14) ◽  
pp. 2491-2499 ◽  
Author(s):  
Elzbieta Pluskota ◽  
Yi Ma ◽  
Kamila M. Bledzka ◽  
Katarzyna Bialkowska ◽  
Dmitry A. Soloviev ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Endothelial Cell Surface ◽  
Catabolic Enzymes ◽  
Key Points ◽  
Cd73 Expression ◽  
Dependent Mechanism

Key Points Kindlin-2 regulates hemostasis in vivo by limiting CD39 and CD73 expression on the surface of endothelial cells. Kindlin-2 interacts directly with CHC and controls clathrin-dependent CD39 and CD73 endocytosis/recycling in endothelial cells.

scholarly journals A Dedifferentiated Sinusoidal Endothelium Impacts Liver-Directed Gene Transfer in Hemophilia-a Mice

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3981-3981
Author(s):  
Shweta Gudapati ◽  
Tomasz W. Kaminski ◽  
Ravi Vats ◽  
Prithu Sundd ◽  
Tirthadipa Pradhan-Sundd
Keyword(s):  
Gene Therapy ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Gene Transfer ◽  
Intravenous Infusion ◽  
Research Funding ◽  
Hemophilia A ◽  
Null Mouse ◽  
Liver Sinusoidal Endothelial Cells ◽  
Sinusoidal Endothelial Cells

Abstract Hemophilia A is an X-linked recessive bleeding disorder that affects 1 in 5000 males and is caused by procoagulant factor VIII deficiency. Affected people are at danger of spontaneous bleeding into organs, which can be fatal and lead to persistent damage. Current therapy includes intravenous infusion of FVIII protein concentrate which carries the danger of transmitting blood-borne diseases. As a result of recent advancements in liver-directed gene transfer, gene therapy based innovative strategy for treating hemophilia has emerged. In patients with severe hemophilia B, intravenous infusion of an adeno-associated viral (AAV) vector encoding factor IX (FIX) under the control of a liver-directed promoter resulted in expression of FIX for a considerable period of time. In hemophilia-A patients, gene treatment utilizing AAV vectors has demonstrated to be less effective than Hemophilia B due to the size of the F8 coding sequence and the decreased release of FVIII protein. Among other concerns high immunogenicity of FVIII with 25-30% of hemophilia A patients forming inhibitors and overexpression of FVIII in hepatocytes triggering a cellular stress response are significantly challenging. A phase 1 clinical trial is now being conducted to examine the AAV8 induced liver directed gene expression strategy to circumvent these challenges. The Factor VIII null mouse has been effective in understanding the disease pathogenesis as well as the development of liver directed novel gene therapy techniques to treat hemophilia. FVIII is predominantly produced in the liver. Thus, liver directed adenoviral and retroviral vectors have been studied by several groups to understand the gene delivery method in hemophilia. A few of these studies have shown limited effectiveness in hemophilia animal models. Although the coagulation anomaly seen in hemophilia murine model was completely repaired immediately after liver directed adenovirus-mediated treatment, the effect was transient. Additionally, adeno associated virus (AAV8)-FVIII overexpression has been associated with increased cellular stress. In this study we evaluated the stability and efficacy of liver driven gene transfer mechanism in FVIII null mouse using recombinant AAV8 vector. Recombinant AAV8 vector delivered through the systemic circulation successfully transduces to target tissues via passing through the permeable barrier of sinusoidal endothelial cell. The bidirectional passage through sinusoidal endothelial cell is mainly supported by the presence of discontinuous fenestrated endothelium. Remarkably, we found that liver directed gene transfer was significantly delayed in FVIII null mice. Using quantitative liver intravital imaging we found that upon AAV8-GFP administration liver sinusoidal endothelial cells shows increased apoptosis. Moreover, structural analysis of the liver sinusoidal endothelial cells using intravital and electron micrograph imaging showed significant structural functional difference in liver sinusoidal endothelial cells of FVIII KO mouse. Work is currently underway to understand how absence of FVIII can affect the LSECs. In conclusion, detailed molecular characterization of LSEC-mediated liver directed gene transfer in a hemophilia mouse model is critical for understanding the efficacy and stability of gene-based hemophilia treatment. Disclosures Sundd: Bayer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring Inc: Research Funding.

An Electron Microscopic Study of Platelet Thrombus Formation in the Rabbit with Particular Regard to 5-Hydroxytryptamine Release

1967 ◽  
Vol 18 (03/04) ◽  
pp. 592-604 ◽  
Author(s):  
H. R Baumgartner ◽  
J. P Tranzer ◽  
A Studer
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Vessel Wall ◽  
Thrombus Formation ◽  
Endothelial Damage ◽  
Electron Microscopic ◽  
Rabbit Ear ◽  
Basement Lamina ◽  
Platelet Thrombus

SummaryElectron microscopic and histologic examination of rabbit ear vein segments 4 and 30 min after slight endothelial damage have yielded the following findings :1. Platelets do not adhere to damaged endothelial cells.2. If the vessel wall is denuded of the whole endothelial cell, platelets adhere to the intimai basement lamina as do endothelial cells.3. The distance between adherent platelets as well as endothelial cells and intimai basement lamina measures 10 to 20 mµ, whereas the distance between aggregated platelets is 30 to 60 mµ.4. 5-hydroxytryptamine (5-HT) is released from platelets during viscous metamorphosis at least in part as 5-HT organelles.It should be noted that the presence of collagen fibers is not necessary for platelet thrombus formation in vivo.

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