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Role of liver sinusoidal endothelial cells in liver diseases

Nature Reviews Gastroenterology & Hepatology volume 18, pages 411–431 (2021)Cite this article

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Abstract

Liver sinusoidal endothelial cells (LSECs) form the wall of the hepatic sinusoids. Unlike other capillaries, they lack an organized basement membrane and have cytoplasm that is penetrated by open fenestrae, making the hepatic microvascular endothelium discontinuous. LSECs have essential roles in the maintenance of hepatic homeostasis, including regulation of the vascular tone, inflammation and thrombosis, and they are essential for control of the hepatic immune response. On a background of acute or chronic liver injury, LSECs modify their phenotype and negatively affect neighbouring cells and liver disease pathophysiology. This Review describes the main functions and phenotypic dysregulations of LSECs in liver diseases, specifically in the context of acute injury (ischaemia–reperfusion injury, drug-induced liver injury and bacterial and viral infection), chronic liver disease (metabolism-associated liver disease, alcoholic steatohepatitis and chronic hepatotoxic injury) and hepatocellular carcinoma, and provides a comprehensive update of the role of LSECs as therapeutic targets for liver disease. Finally, we discuss the open questions in the field of LSEC pathobiology and future avenues of research.

Key points

  • Liver sinusoidal endothelial cells (LSECs) form the vascular wall of the hepatic microcirculatory system, the hepatic sinusoid, and exhibit unique phenotypic characteristics, including open fenestrae and lack of a basement membrane.

  • In health, LSECs have key roles maintaining hepatic homeostasis and are critical for several processes, including immune regulation, control of inflammation, modulation of vascular tone and regulation of the coagulation cascade.

  • LSECs become rapidly dedifferentiated during acute and chronic liver injuries, acquiring vasoconstrictor, proinflammatory and prothrombotic properties; this process, termed ‘capillarization’, contributes to the activation and dedifferentiation of other hepatic cells.

  • LSEC capillarization plays a key part in the pathophysiology of major liver diseases, including ischaemia–reperfusion injury, drug-induced liver injury, chronic liver disease and hepatocellular carcinoma; several LSEC molecular targets have been proposed as treatments.

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Fig. 1: LSECs under physiological conditions maintain liver homeostasis.
Fig. 2: Pathobiology of LSECs in acute liver injury.
Fig. 3: Pathobiology of LSECs in bacterial and viral infection.
Fig. 4: Pathobiology of LSECs in chronic liver disease.
Fig. 5: Pathobiology of LSECs in hepatocellular carcinoma.

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Acknowledgements

The authors acknowledge current and former members of the Liver Vascular Biology Research Group at IDIBAPS-Hospital Clínic de Barcelona and Inselspital-Bern and the Hepatic and Intestinal Immunobiology Group at Miguel Hernández University for their contributions and commitment towards basic and translational liver research; the funding agencies supporting the authors’ research, mainly the Spanish Ministry of Science and Innovation, the Instituto de Salud Carlos III, CIBEREHD, Generalitat de Catalunya, Generalitat Valenciana and the Swiss National Science Foundation (currently AES PI20/00220 and PI16/0967, PID2019-107036RB-I00, AGAUR-SGR2017-517, the CERCA Program, PROMETEO 2016/001 and SNF 320030_189252/1); and the International Society for Hepatic Sinusoidal Research (ISHSR) for its support of sinusoidal research and discussion.

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  1. These authors contributed equally: Jordi Gracia-Sancho, Esther Caparrós, Anabel Fernández-Iglesias, Rubén Francés.

Authors and Affiliations

  1. Liver Vascular Biology Research Group, IDIBAPS Biomedical Research Institute, Barcelona, Spain

    Jordi Gracia-Sancho & Anabel Fernández-Iglesias

  2. CIBEREHD, Instituto de Salud Carlos III, Madrid, Spain

    Jordi Gracia-Sancho, Esther Caparrós, Anabel Fernández-Iglesias & Rubén Francés

  3. Hepatology, Department of Biomedical Research, Inselspital and University of Bern, Bern, Switzerland

    Jordi Gracia-Sancho

  4. Hepatic and Intestinal Immunobiology Group, Department of Clinical Medicine, Miguel Hernández University, San Juan de Alicante, Spain

    Esther Caparrós & Rubén Francés

  5. Instituto ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain

    Esther Caparrós & Rubén Francés

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Gracia-Sancho, J., Caparrós, E., Fernández-Iglesias, A. et al. Role of liver sinusoidal endothelial cells in liver diseases. Nat Rev Gastroenterol Hepatol 18, 411–431 (2021). https://doi.org/10.1038/s41575-020-00411-3

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