Elsevier

Journal of Hepatology

Volume 66, Issue 1, January 2017, Pages 212-227
Journal of Hepatology

Review
Liver sinusoidal endothelial cells: Physiology and role in liver diseases

https://doi.org/10.1016/j.jhep.2016.07.009Get rights and content

Summary

Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells representing the interface between blood cells on the one side and hepatocytes and hepatic stellate cells on the other side. LSECs represent a permeable barrier. Indeed, the association of ‘fenestrae’, absence of diaphragm and lack of basement membrane make them the most permeable endothelial cells of the mammalian body. They also have the highest endocytosis capacity of human cells. In physiological conditions, LSECs regulate hepatic vascular tone contributing to the maintenance of a low portal pressure despite the major changes in hepatic blood flow occurring during digestion. LSECs maintain hepatic stellate cell quiescence, thus inhibiting intrahepatic vasoconstriction and fibrosis development. In pathological conditions, LSECs play a key role in the initiation and progression of chronic liver diseases. Indeed, they become capillarized and lose their protective properties, and they promote angiogenesis and vasoconstriction. LSECs are implicated in liver regeneration following acute liver injury or partial hepatectomy since they renew from LSECs and/or LSEC progenitors, they sense changes in shear stress resulting from surgery, and they interact with platelets and inflammatory cells. LSECs also play a role in hepatocellular carcinoma development and progression, in ageing, and in liver lesions related to inflammation and infection. This review also 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. Finally, this review provides an overview of the strategies available for a specific targeting of LSECs.

Introduction

The vascular endothelium, representing the interface between blood and other tissues, is not only a physical barrier, but contributes to different physiological and pathological processes, including hemostasis/thrombosis, metabolites transportation, inflammation, angiogenesis and vascular tone [1]. Liver sinusoidal endothelial cells (LSECs) form the wall of the liver sinusoids and represent approximately 15 to 20% of liver cells but only 3% of the total liver volume [2]. LSECs are highly specialized endothelial cells. They have a discontinuous architecture meaning that fusion of the luminal and abluminal plasma membrane occurs at other sites than cell junctions, in areas called ‘fenestrae’. This review focuses on the role of LSECs in physiological conditions and their involvement in liver diseases.

Section snippets

Formation of sinusoids during embryogenesis

As illustrated in Fig. 1, an early structural differentiation of hepatic sinusoids occurs between gestational weeks 5 and 12 in human embryos [3]. During that period, LSECs gradually loose cell markers of continuous endothelial cells including platelet endothelial adhesion molecule-1 (PECAM-1, also called cluster of differentiation (CD)31), CD34 and 1F10 antigen, and acquire markers of adult sinusoidal cells including CD4, CD32 and the intracellular adhesion molecule-1 (ICAM-1). This

Markers of LSEC

There is no unique specific marker of LSECs, apart from their fenestrae devoid of diaphragm in the absence of basement membrane. A combination of markers is thus mandatory for their identification.

Identification and isolation of LSECs is a major challenge for the understanding of liver physiology and diseases. However, technical barriers as well as a lack of consensual specific LSEC markers explain that LSECs populations differ between research groups, which limits the interpretation and the

Chronic liver diseases

LSECs play a key role in chronic liver disease initiation and progression, through four processes: sinusoid capillarization, angiogenesis, angiocrine signals and vasoconstriction.

The loss of the specific phenotype of LSECs, including the disappearance of the fenestrae, the development of a basement membrane, and the appearance of specific markers is called capillarization and is an early even in chronic liver injury. When capillarized, LSECs lose their capacity to inactivate hepatic stellate

Conclusion

In conclusion, LSECs have a unique highly permeable phenotype allowing the passage of certain but not all molecules and cells. They also have a very special localization at the interface between blood cells on the one side and hepatocytes and hepatic stellate cells on the other side. LSECs are in constant interaction with other liver cells [83]. LSECs are implicated in most liver diseases including chronic liver disease initiation and progression, hepatocellular carcinoma development and

Financial support

This work was supported by the Agence Nationale pour la Recherche (ANR-14-CE12-0011 and ANR-14-CE35-0022) and by the Association Francaise pour l’Etude du foie (AFEF 2014) and J.P by the “poste d’accueil INSERM”.

Conflict of interest

The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

Authors’ contributions

JP, SL and PER drafted the manuscript. FD, CMB, RM and DV discussed and critically revised the manuscript.

Acknowledgments

We thank Servier medical art for providing some images included in the figures.

References (172)

  • D.G. Le Couteur et al.

    Hepatic pseudocapillarisation and atherosclerosis in ageing

    Lancet

    (2002)
  • C.Q. Fan et al.

    Sinusoidal obstruction syndrome (hepatic veno-occlusive disease)

    J Clin Exp Hepatol

    (2014)
  • P. Krause et al.

    Hepatocyte-supported serum-free culture of rat liver sinusoidal endothelial cells

    J Hepatol

    (2000)
  • S. Motoyama et al.

    Hydrogen peroxide derived from hepatocytes induces sinusoidal endothelial cell apoptosis in perfused hypoxic rat liver

    Gastroenterology

    (1998)
  • S. Hering et al.

    Immortalization of human fetal sinusoidal liver cells by polyoma virus large T antigen

    Exp Cell Res

    (1991)
  • D.W. Kennedy et al.

    Kinetics of central nervous system microglial and macrophage engraftment: analysis using a transgenic bone marrow transplantation model

    Blood

    (1997)
  • F. Schaffner et al.

    Capillarization of hepatic sinusoids in man

    Gastroenterology

    (1963)
  • B. Xu et al.

    Capillarization of hepatic sinusoid by liver endothelial cell-reactive autoantibodies in patients with cirrhosis and chronic hepatitis

    Am J Pathol

    (2003)
  • A. Warren et al.

    Marked changes of the hepatic sinusoid in a transgenic mouse model of acute immune-mediated hepatitis

    J Hepatol

    (2007)
  • L.D. DeLeve et al.

    Prevention of hepatic fibrosis in a murine model of metabolic syndrome with nonalcoholic steatohepatitis

    Am J Pathol

    (2008)
  • M. Miyao et al.

    Pivotal role of liver sinusoidal endothelial cells in NAFLD/NASH progression

    Lab Invest

    (2015)
  • G. Marrone et al.

    Sinusoidal communication in liver fibrosis and regeneration

    J Hepatol

    (2016)
  • J.-C. García-Pagán et al.

    Functional aspects on the pathophysiology of portal hypertension in cirrhosis

    J Hepatol

    (2012)
  • D. Thabut et al.

    Intrahepatic angiogenesis and sinusoidal remodeling in chronic liver disease: New targets for the treatment of portal hypertension?

    J Hepatol

    (2010)
  • K. Taura et al.

    Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis

    Gastroenterology

    (2008)
  • S. Coulon et al.

    Evaluation of inflammatory and angiogenic factors in patients with non-alcoholic fatty liver disease

    Cytokine

    (2012)
  • S. Kaur et al.

    Increased number and function of endothelial progenitor cells stimulate angiogenesis by resident liver sinusoidal endothelial cells (SECs) in cirrhosis through paracrine factors

    J Hepatol

    (2012)
  • P.-E. Rautou

    Endothelial progenitor cells in cirrhosis: the more, the merrier?

    J Hepatol

    (2012)
  • S. Francque et al.

    Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture

    Lab Invest

    (2012)
  • J.-J. Chiu et al.

    Effects of disturbed flow on vascular endothelium: pathophysiological basis and clinical perspectives

    Physiol Rev

    (2011)
  • T.J. Walter et al.

    Epithelial VEGF signaling is required in the mouse liver for proper sinusoid endothelial cell identity and hepatocyte zonation in vivo

    Am J Physiol Gastrointest Liver Physiol

    (2014)
  • Y. Takabe et al.

    Immunomagnetic exclusion of E-cadherin-positive hepatoblasts in fetal mouse liver cell cultures impairs morphogenesis and gene expression of sinusoidal endothelial cells

    J Anat

    (2012)
  • N. Shiojiri et al.

    Immunolocalization of extracellular matrix components and integrins during mouse liver development

    Hepatology

    (2004)
  • K. Asahina et al.

    Septum transversum-derived mesothelium gives rise to hepatic stellate cells and perivascular mesenchymal cells in developing mouse liver

    Hepatology

    (2011)
  • K. Bollerot et al.

    The embryonic origins of hematopoietic stem cells: a tale of hemangioblast and hemogenic endothelium

    APMIS

    (2005)
  • J.A. Alva et al.

    VE-Cadherin-Cre-recombinase transgenic mouse: a tool for lineage analysis and gene deletion in endothelial cells

    Dev Dyn

    (2006)
  • E. Oberlin et al.

    Definitive human and mouse hematopoiesis originates from the embryonic endothelium: a new class of HSCs based on VE-cadherin expression

    Int J Dev Biol

    (2010)
  • A. Martinez-Hernandez et al.

    The hepatic extracellular matrix. II. Ontogenesis, regeneration and cirrhosis

    Virchows Arch

    (1993)
  • N. Shiojiri et al.

    Preferential expression of connexin37 and connexin40 in the endothelium of the portal veins during mouse liver development

    Cell Tissue Res

    (2006)
  • Y. Sugiyama et al.

    Sinusoid development and morphogenesis may be stimulated by VEGF-Flk-1 signaling during fetal mouse liver development

    Dev Dyn

    (2010)
  • H. Zhang et al.

    Genetic lineage tracing identifies endocardial origin of liver vasculature

    Nat Genet

    (2016)
  • P.F. Davies et al.

    The atherosusceptible endothelium: endothelial phenotypes in complex haemodynamic shear stress regions in vivo

    Cardiovasc Res

    (2013)
  • L.D. DeLeve

    Liver sinusoidal endothelial cells and liver regeneration

    J Clin Invest

    (2013)
  • A. Margreet De Leeuw et al.

    Sinusoidal endothelial cells of the liver: Fine structure and function in relation to age

    J Electron Microsc Tech

    (1990)
  • L. Wang et al.

    Liver sinusoidal endothelial cell progenitor cells promote liver regeneration in rats

    J Clin Invest

    (2012)
  • L.D. DeLeve et al.

    Vascular liver disease – mechanisms and management

    (2011)
  • S.S. Lee et al.

    Postprandial hemodynamic responses in patients with cirrhosis

    Hepatology

    (1988)
  • P.F. Davies

    Flow-mediated endothelial mechanotransduction

    Physiol Rev

    (1995)
  • J. Gracia-Sancho et al.

    Endothelial expression of transcription factor Kruppel-like factor 2 and its vasoprotective target genes in the normal and cirrhotic rat liver

    Gut

    (2011)
  • K.M. Parmar et al.

    Integration of flow-dependent endothelial phenotypes by Kruppel-like factor 2

    J Clin Invest

    (2006)
  • Cited by (0)

    These authors contributed equally as joint first authors.

    View full text