Role of liver sinusoidal endothelial cells in liver diseases

Gracia‐Sancho, Jordi; Caparrós, Esther; Fernández‐Iglesias, Anabel; Francés, Rubén

doi:10.1038/s41575-020-00411-3

Cited by 228 publications

(181 citation statements)

References 330 publications

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“…LSECs are known to elicit a pivotal role in the maintenance and regulation of the liver milieu. Indeed, they possess a unique phenotype and are involved in the regulation of multiple biological processes such as angiogenesis, vascular regulation of sinusoidal blood flow, monitoring of gut microbial products and regulation of the immune response along with HMΦs [36,37]. They constitute the liver's first line of defense and the injury-borne endothelial dysfunction has been described as a main driver of the processes related to HSCs activation and the establishment of PH [5].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Profiling of the Liver Sinusoidal Endothelium during Cirrhosis Reveals Stage-Specific Secretory Signature

Manicardi

Fernández‐Iglesias

Abad-Jordà

et al. 2021

Cancers

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The poor prognosis of chronic liver disease (CLD) generates the need to investigate the evolving mechanisms of disease progression, thus disclosing therapeutic targets before development of clinical complications. Considering the central role of liver sinusoidal endothelial cells (LSECs) in pre-neoplastic advanced CLD, the present study aimed at investigating the progression of CLD from an endothelial holistic perspective. RNAseq defined the transcriptome of primary LSECs isolated from three pre-clinical models of advanced CLD, during the progression of the disease, and from fresh human cirrhotic tissue. At each stage of the disease, the effects of LSECs secretome on neighboring cells and proteomic analysis of LSECs-derived extracellular vesicles (EVs) were also determined. CLD was associated with deep common modifications in the transcriptome of LSECs in the pre-clinical models. Pathway enrichment analysis showed predominance of genes related with pro-oncogenic, cellular communication processes, and EVs biogenesis during CLD progression. Crosstalk experiments revealed endothelial EVs as potent angiocrine effectors. The proteome of LSECs EVs showed stage-specific signatures, including over-expression of tropomyosin-1. Proof-of-principle experiments treating cirrhotic HSCs with recombinant tropomyosin-1 suggested de-activating effects. Our data provide the basis for discovering novel biomarkers and therapeutic targets for new disease-modifying treatments for patients with advanced CLD.

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Section: Discussionmentioning

confidence: 99%

Transcriptomic Profiling of the Liver Sinusoidal Endothelium during Cirrhosis Reveals Stage-Specific Secretory Signature

Manicardi

Fernández‐Iglesias

Abad-Jordà

et al. 2021

Cancers

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“…Liver sinusoidal endothelial cells are the first line of defense in the liver and alterations in LSEC play a crucial role in the development of many liver diseases such as fibrosis, cirrhosis, or cancer ( Gracia-Sancho et al, 2021 ) as well as in the age-related conditions ( Hunt et al, 2018 ). To better understand this role, many animal models have been used.…”

Section: Lsec and Drug Interactionsmentioning

confidence: 99%

“…The first part of this review fucuses on the reported influence of drugs on LSEC fenestration number and porosity, while the second part gives a deeper knowledge about fenestration biology and mechanisms behind structure, formation and maintenance of fenestration. This review does not cover a number of other aspects of LSEC biology, but these can be found in in the following excellent reviews about LSEC in: diseases ( Gracia-Sancho et al, 2021 ; Wang and Peng, 2021 ), hepatic fibrosis ( DeLeve, 2015 ), mechanotransduction ( Shu et al, 2021 ), inflammation and cancer ( Wilkinson et al, 2020 ; Yang and Zhang, 2021 ), receptor expression ( Pandey et al, 2020 ), immunological functions ( Shetty et al, 2018 ), aging ( Hunt et al, 2019 ), scavenging ( Sørensen et al, 2012 ), and overall biology of LSECs ( Sørensen et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

The wHole Story About Fenestrations in LSEC

et al. 2021

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The porosity of liver sinusoidal endothelial cells (LSEC) ensures bidirectional passive transport of lipoproteins, drugs and solutes between the liver capillaries and the liver parenchyma. This porosity is realized via fenestrations – transcellular pores with diameters in the range of 50–300 nm – typically grouped together in sieve plates. Aging and several liver disorders severely reduce LSEC porosity, decreasing their filtration properties. Over the years, a variety of drugs, stimulants, and toxins have been investigated in the context of altered diameter or frequency of fenestrations. In fact, any change in the porosity, connected with the change in number and/or size of fenestrations is reflected in the overall liver-vascular system crosstalk. Recently, several commonly used medicines have been proposed to have a beneficial effect on LSEC re-fenestration in aging. These findings may be important for the aging populations of the world. In this review we collate the literature on medicines, recreational drugs, hormones and laboratory tools (including toxins) where the effect LSEC morphology was quantitatively analyzed. Moreover, different experimental models of liver pathology are discussed in the context of fenestrations. The second part of this review covers the cellular mechanisms of action to enable physicians and researchers to predict the effect of newly developed drugs on LSEC porosity. To achieve this, we discuss four existing hypotheses of regulation of fenestrations. Finally, we provide a summary of the cellular mechanisms which are demonstrated to tune the porosity of LSEC.

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“…In response to liver injury, liver sinusoidal endothelial cells (LSECs) also rapidly de-differentiate, acquiring a so-called 'capillarized' phenotype that is characterized by loss of fenestrae, development of a basement membrane, reduced nitric oxide bioavailability and production of proinflammatory, profibrogenic and vasoconstrictor factors that dysregulate neighboring cells (especially HSC) and alter the sinusoidal microcirculation [45,46]. The LSEC and associated sinusoidal communications are therefore also a prime target for antifibrotic and portal hypertension therapy.…”

Section: Scientific Rationalementioning

confidence: 99%

Emerging synthetic drugs for the treatment of liver cirrhosis

Fallowfield

Jimenez-Ramos

Robertson

2021

Expert Opinion on Emerging Drugs

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Introduction:The number of deaths and prevalent cases of cirrhosis are increasing worldwide, but there are no licensed antifibrotic or pro-regenerative medicines and liver transplantation is a limited resource. Cirrhosis is characterized by extreme liver fibrosis, organ dysfunction, and complications related to portal hypertension. Advances in our understanding of liver fibrosis progression and regression following successful etiological therapy betray vulnerabilities in common and disease-specific mechanisms that could be targeted pharmacologically. Area covered: This review summarizes the cellular and molecular pathogenesis of cirrhosis as a preface to discussion of the current drug development landscape. The dominant indication for global pharma R&D pipelines is cirrhosis related to nonalcoholic steatohepatitis (NASH). We searched Clinicaltrials.gov, GlobalData, Pharmaprojects and PubMed for pertinent information on emerging synthetic drugs for cirrhosis, with a focus on compounds listed in phase 2 and phase 3 trials. Expert opinion: Although cirrhosis can regress following successful etiological treatment, there are no specific antifibrotic or pro-regenerative drugs approved for this condition. Obstacles to drug development in cirrhosis include intrinsic biological factors, a heterogeneous patient population, and lack of acceptable surrogate endpoints. Nevertheless, several synthetic drugs are being evaluated in clinical trials and the NASH field is rapidly embracing a drug combination approach.

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Role of liver sinusoidal endothelial cells in liver diseases

Cited by 228 publications

References 330 publications

Transcriptomic Profiling of the Liver Sinusoidal Endothelium during Cirrhosis Reveals Stage-Specific Secretory Signature

Transcriptomic Profiling of the Liver Sinusoidal Endothelium during Cirrhosis Reveals Stage-Specific Secretory Signature

The wHole Story About Fenestrations in LSEC

Emerging synthetic drugs for the treatment of liver cirrhosis

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