Liver sinusoidal endothelial cells: Physiology and role in liver diseases.
TL;DR: This review provides an overview of the strategies available for a specific targeting of LSECs and presents a detailed analysis of the technical aspects relevant for LSEC analysis including the markers these cells express, the available cell lines and the transgenic mouse models.
About: This article is published in Journal of Hepatology.The article was published on 2017-01-01. It has received 561 citations till now. The article focuses on the topics: Hepatic stellate cell & Liver regeneration.
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TL;DR: Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation of hepatic stellate cells will enable more effective and less toxic precision antifibrotic therapies.
770 citations
TL;DR: An atlas of >32,000 single-EC transcriptomes from 11 mouse tissues was constructed and 78 EC subclusters were identified, including Aqp7+ intestinal capillaries and angiogenic ECs in healthy tissues and provides a powerful discovery tool and resource value.
624 citations
TL;DR: This review will analyze the most relevant established and/or emerging pathophysiological issues underlying CLD progression with a focus on the role of critical hepatic cell populations, mechanisms and signaling pathways involved, as they represent potential therapeutic targets to finally analyze selected and relevant clinical issues.
479 citations
Cites background from "Liver sinusoidal endothelial cells:..."
...no human data is available concerning the specific targeting of LSEC, which are known to maintain HSC in a quiescent phenotype (Poisson et al., 2017) although positive results...
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TL;DR: This Review comprehensively covers recent landmark discoveries pertaining to the organotypically specialized (micro)vasculature in different organs and highlights the properties of blood vessels in the brain, eyes, heart, lungs, liver, kidneys, bones, adipose tissue, and endocrine glands.
Abstract: Blood vessels form one of the body's largest surfaces, serving as a critical interface between the circulation and the different organ environments. They thereby exert gatekeeper functions on tissue homeostasis and adaptation to pathologic challenge. Vascular control of the tissue microenvironment is indispensable in development, hemostasis, inflammation, and metabolism, as well as in cancer and metastasis. This multitude of vascular functions is mediated by organ-specifically differentiated endothelial cells (ECs), whose cellular and molecular heterogeneity has long been recognized. Yet distinct organotypic functional attributes and the molecular mechanisms controlling EC differentiation and vascular bed-specific functions have only become known in recent years. Considering the involvement of vascular dysfunction in numerous chronic and life-threatening diseases, a better molecular understanding of organotypic vasculatures may pave the way toward novel angiotargeted treatments to cure hitherto intractable diseases. This Review summarizes recent progress in the understanding of organotypic vascular differentiation and function.
443 citations
TL;DR: The emergence of NASH-associated macrophages (NAMs) is uncovered, which is marked by high expression of triggering receptors expressed on myeloid cells 2 (Trem2), as a feature of mouse and human NASH that is linked to disease severity and highly responsive to pharmacological and dietary interventions.
412 citations
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TL;DR: Preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies.
Abstract: Blood vessels deliver oxygen and nutrients to every part of the body, but also nourish diseases such as cancer. Over the past decade, our understanding of the molecular mechanisms of angiogenesis (blood vessel growth) has increased at an explosive rate and has led to the approval of anti-angiogenic drugs for cancer and eye diseases. So far, hundreds of thousands of patients have benefited from blockers of the angiogenic protein vascular endothelial growth factor, but limited efficacy and resistance remain outstanding problems. Recent preclinical and clinical studies have shown new molecular targets and principles, which may provide avenues for improving the therapeutic benefit from anti-angiogenic strategies.
4,441 citations
"Liver sinusoidal endothelial cells:..." refers background in this paper
...Angiogenesis is defined by the development of new vessels from preexistent vessels [87]....
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TL;DR: The transmission of hemodynamic forces throughout the endothelium and the mechanotransduction mechanisms that lead to biophysical, biochemical, and gene regulatory responses of endothelial cells to hemodynamic shear stresses are reviewed.
Abstract: Mechanical forces associated with blood flow play important roles in the acute control of vascular tone, the regulation of arterial structure and remodeling, and the localization of atherosclerotic lesions. Major regulation of the blood vessel responses occurs by the action of hemodynamic shear stresses on the endothelium. The transmission of hemodynamic forces throughout the endothelium and the mechanotransduction mechanisms that lead to biophysical, biochemical, and gene regulatory responses of endothelial cells to hemodynamic shear stresses are reviewed.
2,719 citations
"Liver sinusoidal endothelial cells:..." refers background in this paper
...Intrahepatic shear stress is recognized as a main driver of hepatic blood flow regulation [26]....
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...Shear stress is a frictional force applied by blood flow on endothelial surface [26]....
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...It is proportional to flow intensity and to blood viscosity and inversely proportional to the cubic radius of the vessel [26]....
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TL;DR: Current knowledge on the role of disturbed flow in EC physiology and pathophysiology, as well as its clinical implications are summarized to contribute to the understanding of the etiology of lesion development in vascular niches with disturbed flow and help to generate new approaches for therapeutic interventions.
Abstract: Vascular endothelial cells (ECs) are exposed to hemodynamic forces, which modulate EC functions and vascular biology/pathobiology in health and disease. The flow patterns and hemodynamic forces are not uniform in the vascular system. In straight parts of the arterial tree, blood flow is generally laminar and wall shear stress is high and directed; in branches and curvatures, blood flow is disturbed with nonuniform and irregular distribution of low wall shear stress. Sustained laminar flow with high shear stress upregulates expressions of EC genes and proteins that are protective against atherosclerosis, whereas disturbed flow with associated reciprocating, low shear stress generally upregulates the EC genes and proteins that promote atherogenesis. These findings have led to the concept that the disturbed flow pattern in branch points and curvatures causes the preferential localization of atherosclerotic lesions. Disturbed flow also results in postsurgical neointimal hyperplasia and contributes to pathophysiology of clinical conditions such as in-stent restenosis, vein bypass graft failure, and transplant vasculopathy, as well as aortic valve calcification. In the venous system, disturbed flow resulting from reflux, outflow obstruction, and/or stasis leads to venous inflammation and thrombosis, and hence the development of chronic venous diseases. Understanding of the effects of disturbed flow on ECs can provide mechanistic insights into the role of complex flow patterns in pathogenesis of vascular diseases and can help to elucidate the phenotypic and functional differences between quiescent (nonatherogenic/nonthrombogenic) and activated (atherogenic/thrombogenic) ECs. This review summarizes the current knowledge on the role of disturbed flow in EC physiology and pathophysiology, as well as its clinical implications. Such information can contribute to our understanding of the etiology of lesion development in vascular niches with disturbed flow and help to generate new approaches for therapeutic interventions.
1,699 citations
TL;DR: Modulation of TGF-β signaling by a TLR4-MyD88–NF-κB axis provides a novel link between proinflammatory and profibrogenic signals.
Abstract: Hepatic injury is associated with a defective intestinal barrier and increased hepatic exposure to bacterial products. Here we report that the intestinal bacterial microflora and a functional Toll-like receptor 4 (TLR4), but not TLR2, are required for hepatic fibrogenesis. Using Tlr4-chimeric mice and in vivo lipopolysaccharide (LPS) challenge, we demonstrate that quiescent hepatic stellate cells (HSCs), the main precursors for myofibroblasts in the liver, are the predominant target through which TLR4 ligands promote fibrogenesis. In quiescent HSCs, TLR4 activation not only upregulates chemokine secretion and induces chemotaxis of Kupffer cells, but also downregulates the transforming growth factor (TGF)-beta pseudoreceptor Bambi to sensitize HSCs to TGF-beta-induced signals and allow for unrestricted activation by Kupffer cells. LPS-induced Bambi downregulation and sensitization to TGF-beta is mediated by a MyD88-NF-kappaB-dependent pathway. Accordingly, Myd88-deficient mice have decreased hepatic fibrosis. Thus, modulation of TGF-beta signaling by a TLR4-MyD88-NF-kappaB axis provides a novel link between proinflammatory and profibrogenic signals.
1,604 citations
TL;DR: Tie2-Cre transgenic mice are a new genetic tool for the analyses of endothelial cell-lineage and endothelialcell-specific gene targeting and lacZ staining in Tie2- Cre;CAG-CAT-Z embryos is consistent with endocardial-mesenchymal transformation in the atrioventricular canal and outflow tract regions.
1,153 citations