Angiocrine signaling in the hepatic sinusoids in health and disease

The capillary network irrigating the liver is important not only for nutrient and oxygen delivery, but also for the signals distributed to other hepatic cell types necessary to maintain liver homeostasis. During development, endothelial cells are a key component in liver zonation. In adulthood, they maintain hepatic stellate cells and hepatocytes in quiescence. Their importance in pathobiology is highlighted in liver regeneration and chronic liver diseases, where they coordinate paracrine cell behavior. During regeneration, liver sinusoidal endothelial cells induce hepatocyte proliferation and angiogenesis. During fibrogenesis, they undergo morphological and functional changes, which are reflected by their role in hepatic stellate cell activation, inflammation, and distorted sinusoidal structure. Therapeutic strategies to target angiocrine signaling are in progress but are in the early stages. Here, we offer a short synthesis of recent studies on angiocrine signaling in liver homeostasis, regeneration, and fibrogenesis.

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The Endothelium as a Driver of Liver Fibrosis and Regeneration

Cells ◽

10.3390/cells9040929 ◽

2020 ◽

Vol 9 (4) ◽

pp. 929 ◽

Cited By ~ 7

Author(s):

Erica Lafoz ◽

Maria Ruart ◽

Aina Anton ◽

Anna Oncins ◽

Virginia Hernández-Gea

Keyword(s):

Endothelial Cells ◽

Liver Fibrosis ◽

Liver Injury ◽

Stellate Cell ◽

Public Health Problem ◽

Cell Types ◽

Regenerative Process ◽

Research Field ◽

Major Public Health Problem ◽

Liver Sinusoidal Endothelial Cells

Liver fibrosis is a common feature of sustained liver injury and represents a major public health problem worldwide. Fibrosis is an active research field and discoveries in the last years have contributed to the development of new antifibrotic drugs, although none of them have been approved yet. Liver sinusoidal endothelial cells (LSEC) are highly specialized endothelial cells localized at the interface between the blood and other liver cell types. They lack a basement membrane and display open channels (fenestrae), making them exceptionally permeable. LSEC are the first cells affected by any kind of liver injury orchestrating the liver response to damage. LSEC govern the regenerative process initiation, but aberrant LSEC activation in chronic liver injury induces fibrosis. LSEC are also main players in fibrosis resolution. They maintain liver homeostasis and keep hepatic stellate cell and Kupffer cell quiescence. After sustained hepatic injury, they lose their phenotype and protective properties, promoting angiogenesis and vasoconstriction and contributing to inflammation and fibrosis. Therefore, improving LSEC phenotype is a promising strategy to prevent liver injury progression and complications. This review focuses on changes occurring in LSEC after liver injury and their consequences on fibrosis progression, liver regeneration, and resolution. Finally, a synopsis of the available strategies for LSEC-specific targeting is provided.

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SECs (Sinusoidal Endothelial Cells), Liver Microenvironment, and Fibrosis

BioMed Research International ◽

10.1155/2017/4097205 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 20

Author(s):

Vaishaali Natarajan ◽

Edward N. Harris ◽

Srivatsan Kidambi

Keyword(s):

Endothelial Cells ◽

Liver Fibrosis ◽

Cell Activation ◽

Stellate Cell ◽

Protein Profile ◽

Liver Sinusoidal Endothelial Cells ◽

Sinusoidal Endothelial Cells ◽

Fibrotic Liver ◽

Nonalcoholic Fatty Liver ◽

Functional Features

Liver fibrosis is a wound-healing response to chronic liver injury such as alcoholic/nonalcoholic fatty liver disease and viral hepatitis with no FDA-approved treatments. Liver fibrosis results in a continual accumulation of extracellular matrix (ECM) proteins and paves the way for replacement of parenchyma with nonfunctional scar tissue. The fibrotic condition results in drastic changes in the local mechanical, chemical, and biological microenvironment of the tissue. Liver parenchyma is supported by an efficient network of vasculature lined by liver sinusoidal endothelial cells (LSECs). These nonparenchymal cells are highly specialized resident endothelial cell type with characteristic morphological and functional features. Alterations in LSECs phenotype including lack of LSEC fenestration, capillarization, and formation of an organized basement membrane have been shown to precede fibrosis and promote hepatic stellate cell activation. Here, we review the interplay of LSECs with the dynamic changes in the fibrotic liver microenvironment such as matrix rigidity, altered ECM protein profile, and cell-cell interactions to provide insight into the pivotal changes in LSEC physiology and the extent to which it mediates the progression of liver fibrosis. Establishing the molecular aspects of LSECs in the light of fibrotic microenvironment is valuable towards development of novel therapeutic and diagnostic targets of liver fibrosis.

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The Scavenger Function of Liver Sinusoidal Endothelial Cells in Health and Disease

Frontiers in Physiology ◽

10.3389/fphys.2021.757469 ◽

2021 ◽

Vol 12 ◽

Author(s):

Sabin Bhandari ◽

Anett Kristin Larsen ◽

Peter McCourt ◽

Bård Smedsrød ◽

Karen Kristine Sørensen

Keyword(s):

Endothelial Cells ◽

Cell Activation ◽

Biological Activities ◽

High Capacity ◽

Great Majority ◽

Blood Clearance ◽

Liver Sinusoidal Endothelial Cells ◽

Sinusoidal Endothelial Cells ◽

Waste Products ◽

Health And Disease

The aim of this review is to give an outline of the blood clearance function of the liver sinusoidal endothelial cells (LSECs) in health and disease. Lining the hundreds of millions of hepatic sinusoids in the human liver the LSECs are perfectly located to survey the constituents of the blood. These cells are equipped with high-affinity receptors and an intracellular vesicle transport apparatus, enabling a remarkably efficient machinery for removal of large molecules and nanoparticles from the blood, thus contributing importantly to maintain blood and tissue homeostasis. We describe here central aspects of LSEC signature receptors that enable the cells to recognize and internalize blood-borne waste macromolecules at great speed and high capacity. Notably, this blood clearance system is a silent process, in the sense that it usually neither requires or elicits cell activation or immune responses. Most of our knowledge about LSECs arises from studies in animals, of which mouse and rat make up the great majority, and some species differences relevant for extrapolating from animal models to human are discussed. In the last part of the review, we discuss comparative aspects of the LSEC scavenger functions and specialized scavenger endothelial cells (SECs) in other vascular beds and in different vertebrate classes. In conclusion, the activity of LSECs and other SECs prevent exposure of a great number of waste products to the immune system, and molecules with noxious biological activities are effectively “silenced” by the rapid clearance in LSECs. An undesired consequence of this avid scavenging system is unwanted uptake of nanomedicines and biologics in the cells. As the development of this new generation of therapeutics evolves, there will be a sharp increase in the need to understand the clearance function of LSECs in health and disease. There is still a significant knowledge gap in how the LSEC clearance function is affected in liver disease.

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Abstract 225: Chronic Alcohol Consumption Alters the Epigenetic Fingerprint of Cardiac Cell Types

Circulation Research ◽

10.1161/res.115.suppl_1.225 ◽

2014 ◽

Vol 115 (suppl_1) ◽

Author(s):

Alexander R Mackie ◽

Erin E Vaughan ◽

Mohsin Khan ◽

Suresh K Verma ◽

Srikanth Garikipati ◽

...

Keyword(s):

Endothelial Cells ◽

Ejection Fraction ◽

Cell Types ◽

Chronic Ethanol ◽

Ethanol Ingestion ◽

Specific Gene ◽

Cardiac Cell ◽

Functional Changes ◽

Chronic Ethanol Consumption ◽

High Ethanol

The cardiac influence of chronic ethanol (EtOH) consumption in humans is dictated by the frequency of ethanol ingestion. Whereas moderate consumption (i.e. 1-2 alcoholic drinks/day) imparts a cardiac benefit to patients by reducing adverse cardiovascular event (ACE) occurrences, consumption below or beyond these moderate levels significantly increases the incidence of ACEs. Despite these observations, little is known regarding the functional impact of chronic EtOH consumption on post-myocardial infarct repair or the cellular mechanisms involved in this process. Thus, we investigated the post-AMI functional consequences of chronic ethanol consumption in mice. Mice received chronic ethanol via the Lieber-DeCarli paradigm (i.e. 0%, 1% (moderate) or 5% (high) ethanol v/v) in an isocaloric fashion for 8 weeks. After 8 weeks, mice underwent a 60-minute ischemic/reperfusion injury and the subsequent assessment of their cardiac function for 4 weeks post-AMI. As early as two weeks post-AMI, mice fed the 1% EtOH displayed modest yet significant improvements in ejection fraction and systolic ventricular volumes as compared to control mice. Conversely, the 5% EtOH diet group displayed diminished ejection fraction and increases in both systolic chamber volume and infarct size. To explore the cellular basis of these observed functional changes, primary cardiac cell types (fibroblasts and endothelial cells) treated chronically (5 days) with ethanol in vitro (i.e. 0%, 0.1% (moderate) or 0.5% (high) ethanol v/v) displayed robust changes in their epigenetic histone-modification profiles indicating a high likelihood for changes in cell specific gene expression. In addition, conditioned media from ethanol treated primary cardiac fibroblasts (PCFBs) altered the tube forming capacity of endothelial cells in a matrigel tube-formation assay in a dose pattern akin to what was observed in vivo. This data suggests that chronic ethanol directly invokes epigenetic changes in PCFBs that can modify their contribution to cardiac repair processes following AMI. Lastly, we are actively investigating whether ethanol-induced changes to endothelial cell epigenetic patterns alter the cells responses in the face of an ischemic insult.

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Platelet Interactions with Liver Sinusoidal Endothelial Cells and Hepatic Stellate Cells Lead to Hepatocyte Proliferation

Cells ◽

10.3390/cells9051243 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1243 ◽

Cited By ~ 1

Author(s):

Jeremy Meyer ◽

Alexandre Balaphas ◽

Pierre Fontana ◽

Philippe Morel ◽

Simon C. Robson ◽

...

Keyword(s):

Endothelial Cells ◽

Growth Factor ◽

Liver Regeneration ◽

Partial Hepatectomy ◽

Hepatic Stellate Cells ◽

Stellate Cells ◽

Hepatocyte Proliferation ◽

Liver Sinusoidal Endothelial Cells ◽

Hepatocyte Growth

(1) Background: Platelets were postulated to constitute the trigger of liver regeneration. The aim of this study was to dissect the cellular interactions between the various liver cells involved in liver regeneration and to clarify the role of platelets. (2) Methods: Primary mouse liver sinusoidal endothelial cells (LSECs) were co-incubated with increasing numbers of resting platelets, activated platelets, or platelet releasates. Alterations in the secretion of growth factors were measured. The active fractions of platelet releasates were characterized and their effects on hepatocyte proliferation assessed. Finally, conditioned media of LSECs exposed to platelets were added to primary hepatic stellate cells (HSCs). Secretion of hepatocyte growth factor (HGF) and hepatocyte proliferation were measured. After partial hepatectomy in mice, platelet and liver sinusoidal endothelial cell (LSEC) interactions were analyzed in vivo by confocal microscopy, and interleukin-6 (IL-6) and HGF levels were determined. (3) Results: Co-incubation of increasing numbers of platelets with LSECs resulted in enhanced IL-6 secretion by LSECs. The effect was mediated by the platelet releasate, notably a thermolabile soluble factor with a molecular weight over 100 kDa. The conditioned medium of LSECs exposed to platelets did not increase proliferation of primary hepatocytes when compared to LSECs alone but stimulated hepatocyte growth factor (HGF) secretion by HSCs, which led to hepatocyte proliferation. Following partial hepatectomy, in vivo adhesion of platelets to LSECs was significantly increased when compared to sham-operated mice. Clopidogrel inhibited HGF secretion after partial hepatectomy. (4) Conclusion: Our findings indicate that platelets interact with LSECs after partial hepatectomy and activate them to release a large molecule of protein nature, which constitutes the initial trigger for liver regeneration.

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Liver Sinusoidal Endothelial Cells Contribute to Hepatic Antigen-Presenting Cell Function and Th17 Expansion in Cirrhosis

Cells ◽

10.3390/cells9051227 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1227

Author(s):

Esther Caparrós ◽

Oriol Juanola ◽

Isabel Gómez-Hurtado ◽

Amaya Puig-Kroger ◽

Paula Piñero ◽

...

Keyword(s):

Endothelial Cells ◽

T Cell ◽

Bile Duct ◽

T Cell Activation ◽

Cell Activation ◽

Experimental Models ◽

Cd4 T Cell ◽

Liver Sinusoidal Endothelial Cells ◽

Sinusoidal Endothelial Cells ◽

Bacterial Peritonitis

Hepatic immune function is compromised during cirrhosis. This study investigated the immune features of liver sinusoidal endothelial cells (LSECs) in two experimental models of cirrhosis. Dendritic cells, hepatic macrophages, and LSECs were isolated from carbon tetrachloride and bile duct-ligated rats. Gene expression of innate receptors, bacterial internalization, co-stimulatory molecules induction, and CD4+ T cell activation and differentiation were evaluated. Induced bacterial peritonitis and norfloxacin protocols on cirrhotic rats were also carried out. LSECs demonstrated an active immunosurveillance profile, as shown by transcriptional modulation of different scavenger and cell-adhesion genes, and their contribution to bacterial internalization. LSECs significantly increased their expression of CD40 and CD80 and stimulated CD4+ T cell activation marker CD71 in both models. The pro-inflammatory Th17 subset was expanded in CCl4-derived LSECs co-cultures. In the bile duct ligation (BDL) model, CD4+ T cell differentiation only occurred under induced bacterial peritonitis conditions. Differentiated pro-inflammatory Th cells by LSECs in both experimental models were significantly reduced with norfloxacin treatment, whereas Foxp3 tolerogenic Th CD4+ cells were expanded. Conclusion: LSECs’ participation in the innate-adaptive immune progression, their ability to stimulate pro-inflammatory CD4+ T cells expansion during liver damage, and their target role in norfloxacin-induced immunomodulation granted a specific competence to this cell population in cirrhosis.

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Rat liver endothelial cell glutamine transporter and glutaminase expression contrast with parenchymal cells

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1999.276.3.g743 ◽

1999 ◽

Vol 276 (3) ◽

pp. G743-G750 ◽

Cited By ~ 5

Author(s):

Rüdiger Lohmann ◽

Wiley W. Souba ◽

Barrie P. Bode

Keyword(s):

Endothelial Cells ◽

Amino Acid ◽

Cell Types ◽

Male Rats ◽

Specific Cell ◽

Liver Endothelial Cell ◽

Glutamine Transporter ◽

Health And Disease ◽

Parenchymal Cells ◽

Functional Analyses

Despite the central role of the liver in glutamine homeostasis in health and disease, little is known about the mechanism by which this amino acid is transported into sinusoidal endothelial cells, the second most abundant hepatic cell type. To address this issue, the transport ofl-glutamine was functionally characterized in hepatic endothelial cells isolated from male rats. On the basis of functional analyses, including kinetics, cation substitution, and amino acid inhibition, it was determined that a Na+-dependent carrier distinct from system N in parenchymal cells, with properties of system ASC or B0, mediated the majority of glutamine transport in hepatic endothelial cells. These results were supported by Northern blot analyses that showed expression of the ATB0 transporter gene in endothelial but not parenchymal cells. Concurrently, it was determined that, whereas both cell types express glutamine synthetase, hepatic endothelial cells express the kidney-type glutaminase isozyme in contrast to the liver-type isozyme in parenchymal cells. This represents the first report of ATB0 and kidney-type glutaminase isozyme expression in the liver, observations that have implications for roles of specific cell types in hepatic glutamine homeostasis in health and disease.

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Transcriptome and proteome profiling reveal complementary scavenger and immune features of rat liver sinusoidal endothelial cells and liver macrophages

10.21203/rs.2.24396/v3 ◽

2020 ◽

Author(s):

Sabin Bhandari ◽

Ruomei Li ◽

Jaione Simón-Santamaría ◽

Peter McCourt ◽

Steinar Daae Johansen ◽

...

Keyword(s):

Endothelial Cells ◽

Antigen Processing ◽

Constitutive Expression ◽

Cell Types ◽

The Body ◽

Male Rats ◽

Molecular Profile ◽

Immune Functions ◽

Liver Sinusoidal Endothelial Cells ◽

Sinusoidal Endothelial Cells

Abstract Background: Liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs; liver resident macrophages) form the body´s most effective scavenger cell system for the removal of harmful blood-borne substances, ranging from modified self-proteins to pathogens and xenobiotics. Controversies in the literature regarding the LSEC phenotype pose a challenge when determining distinct functionalities of KCs and LSECs. This may be due to overlapping functions of the two cells, insufficient purification and/or identification of the cells, rapid dedifferentiation of LSECs in vitro, or species differences. We therefore characterized and quantitatively compared expressed gene products of freshly isolated, highly pure LSECs (fenestrated SE-1/FcgRIIb2+) and KCs (CD11b/c+) from Sprague Dawley, Crl:CD(SD), male rats using high throughput mRNA-sequencing and label-free proteomics.Results: We observed a robust correlation between the proteomes and transcriptomes of the two cell types. Integrative analysis of the global molecular profile demonstrated the immunological aspects of LSECs. The constitutive expression of several immune genes and corresponding proteins of LSECs bore some resemblance with the expression in macrophages. LSECs and KCs both expressed high levels of scavenger receptors (SR) and C-type lectins. Equivalent expression of SR-A1 (Msr1), mannose receptor (Mrc1), SR-B1 (Scarb1), and SR-B3 (Scarb2) suggested functional similarity between the two cell types, while functional distinction between the cells was evidenced by LSEC-specific expression of the SRs stabilin-1 (Stab1) and stabilin-2 (Stab2), and the C-type lectins LSECtin (Clec4g) and DC-SIGNR (Clec4m). Many immune regulatory factors were differentially expressed in LSECs and KCs, with one cell predominantly expressing a specific cytokine/chemokine and the other cell the cognate receptor, illustrating the complex cytokine milieu of the sinusoids. Both cells expressed genes and proteins involved in antigen processing and presentation, and lymphocyte co-stimulation. Conclusions: Our findings support complementary and partly overlapping scavenging and immune functions of LSECs and KCs. This highlights the importance of including LSECs in studies of liver immunity, and liver clearance and toxicity of large molecule drugs and nano-formulations.

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Extra- and Intra-Cellular Mechanisms of Hepatic Stellate Cell Activation

Biomedicines ◽

10.3390/biomedicines9081014 ◽

2021 ◽

Vol 9 (8) ◽

pp. 1014

Author(s):

Yufei Yan ◽

Jiefei Zeng ◽

Linhao Xing ◽

Changyong Li

Keyword(s):

Signaling Pathways ◽

Hepatic Fibrosis ◽

Cellular Response ◽

Cell Activation ◽

Molecular Mechanisms ◽

Stellate Cell ◽

Hippo Signaling ◽

Liver Sinusoidal Endothelial Cells ◽

Chronic Injury ◽

Lipid Metabolism Disorder

Hepatic fibrosis is characterized by the pathological accumulation of extracellular matrix (ECM) in the liver resulting from the persistent liver injury and wound-healing reaction induced by various insults. Although hepatic fibrosis is considered reversible after eliminating the cause of injury, chronic injury left unchecked can progress to cirrhosis and liver cancer. A better understanding of the cellular and molecular mechanisms controlling the fibrotic response is needed to develop novel clinical strategies. It is well documented that activated hepatic stellate cells (HSCs) is the most principal cellular players promoting synthesis and deposition of ECM components. In the current review, we discuss pathways of HSC activation, emphasizing emerging extra- and intra-cellular signals that drive this important cellular response to hepatic fibrosis. A number of cell types and external stimuli converge upon HSCs to promote their activation, including hepatocytes, liver sinusoidal endothelial cells, macrophages, cytokines, altered ECM, hepatitis viral infection, enteric dysbiosis, lipid metabolism disorder, exosomes, microRNAs, alcohol, drugs and parasites. We also discuss the emerging signaling pathways and intracellular events that individually or synergistically drive HSC activation, including TGFβ/Smad, Notch, Wnt/β-catenin, Hedgehog and Hippo signaling pathways. These findings will provide novel potential therapeutic targets to arrest or reverse fibrosis and cirrhosis.

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Transcellular sulfidopeptide leukotriene biosynthetic capacity of vascular cells

Blood ◽

10.1182/blood.v74.2.703.703 ◽

1989 ◽

Vol 74 (2) ◽

pp. 703-707 ◽

Cited By ~ 55

Author(s):

J Maclouf ◽

RC Murphy ◽

PM Henson

Keyword(s):

Endothelial Cells ◽

Cell Activation ◽

Calcium Ionophore ◽

Cell Types ◽

Fixed Number ◽

Calcium Ionophore A23187 ◽

Ionophore A23187 ◽

Mixed Cell ◽

Wide Range

Abstract Cells in the vasculature, including polymorphonuclear leukocytes, platelets, and endothelial cells, have been shown to be jointly involved in the biosynthesis of active lipid mediators derived from arachidonic acid. Stimulation of neutrophils with the calcium ionophore A23187 as a model for cell activation results in production of leukotriene (LT)A4 with subsequent intracellular conversion into LTB4. When platelets or endothelial cells were present in the incubation system, LTC4 was produced from the neutrophil-derived LTA4. Whereas production and release of LTA4 under resting conditions in vivo might be expected to be quite low, under pathologic conditions, LTA4 production could be markedly increased. Therefore, the metabolism of exogenous LTA4 by platelets and endothelial cells was studied at a wide range of LTA4 concentrations. The production of LTC4 during coincubation of neutrophils with platelets was found to be dependent on neutrophil number ranging from 2 x 10(5) to 2 x 10(7) cells/mL. When a fixed number of neutrophils were stimulated with platelets alone or with mixtures of platelets and endothelial cells, LTC4 production was observed to be dependent on both acceptor cell types. These results suggest that mixed cell populations, which are likely to occur in vivo, may be critical determinants of the profile of eicosanoids produced in pathophysiologic circumstances. We suggest that both endothelial cells and platelets, in the presence of neutrophils, contribute large quantities of sulfidopeptide leukotrienes to inflammatory and thrombotic situations. Furthermore, platelets, because of their quantity and reactivity, may play a pivotal role in transcellular biosynthesis of eicosanoids.

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