Gene Signatures Detect Damaged Liver Sinusoidal Endothelial Cells in Chronic Liver Diseases

Verhulst, Stefaan; Os, Elise Anne van; Smet, Vincent De; Eysackers, Nathalie; Mannaerts, Inge; Grunsven, Leo A. van

doi:10.3389/fmed.2021.750044

Cited by 11 publications

(23 citation statements)

References 67 publications

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“…While various markers such as CD32b, CLEC4G, LYVE1, and STAB2 have emerged for the detection of LSECs in healthy livers, electron microscopy remains the gold standard for the identification of damaged LSECs, as it can detect the loss of basement membrane and fenestrae [ 142 ].…”

Section: Endothelial Cells In the Pathogenesis Of Nafldmentioning

confidence: 99%

“…Recently, single-cell transcriptomic (scRNAseq) analyses in both healthy and diseased human and mouse livers have identified heterogeneity within the LSEC population and several biomarkers to assess disease development [ 142 , 143 ].…”

Section: Endothelial Cells In the Pathogenesis Of Nafldmentioning

confidence: 99%

“…A metagene signature analysis revealed that the expression of profibrogenic genes such as PDGFD , PDGFB , LOX , and LOXL2 in the scar-associated endothelial cells was associated with extracellular matrix rearrangement and increased hepatic fibrillar collagens [ 144 ]. While the expression of LSEC-specific scavenger receptors, including STAB2 , CLEC4G , CD209 , MRC1 , and CD32B , as well as receptors involved in VEGF-induced angiogenesis signaling, such as KDR and NRP1, have been defined as a signature of healthy LSECs [ 142 ], a study by Verhulst and colleagues showed that STAB2 and CLEC4G are reduced during chronic liver diseases [ 142 ]. Transcriptomics revealed that the interaction between LSECs and chemokines was disrupted in mice deficient in STAB1 (Stab1KO) and STAB2 (Stab1KO) due to the reduced expression of adhesion molecules and other molecules involved in cytokine-cytokine receptor interaction [ 145 ].…”

Section: Endothelial Cells In the Pathogenesis Of Nafldmentioning

confidence: 99%

“…Transcriptomics revealed that the interaction between LSECs and chemokines was disrupted in mice deficient in STAB1 (Stab1KO) and STAB2 (Stab1KO) due to the reduced expression of adhesion molecules and other molecules involved in cytokine-cytokine receptor interaction [ 145 ]. Strong expression of both TIMP1 and TIMP2 in LSECs was observed in a single-cell analysis of human livers of both chronic and acute liver injury [ 142 ]. On the contrary, a study by Xiong et al, found no significant changes in the expression of both TIMP1 and TIMP2 , while they detected abundant expression of Fcgr2b and Gpr182 by scRNAseq analysis [ 146 ].…”

Section: Endothelial Cells In the Pathogenesis Of Nafldmentioning

confidence: 99%

“…Apart from the aforementioned markers of LSEC function/dysfunction, the expression of FABP4, fatty acid-binding protein 5 (FAPB5), von Willebrand factor (VWF), von Willebrand factor A domain-containing 1 (VWA1), and CD31 was found to be upregulated in LSECs during liver disease [ 49 , 142 , 148 ]. A single-cell RNAseq analysis by Verhulst and colleagues revealed the upregulation of FABP4/5 and VWF/a1 as a signature of damaged human LSECs [ 142 ]. The expression of FABP4 was found to be elevated during liver fibrosis.…”

Section: Endothelial Cells In the Pathogenesis Of Nafldmentioning

confidence: 99%

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Endothelial Cell Dysfunction and Nonalcoholic Fatty Liver Disease (NAFLD): A Concise Review

Nasiri-Ansari

Ανδρουτσάκος

Flessa

et al. 2022

Cells

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Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide. It is strongly associated with obesity, type 2 diabetes (T2DM), and other metabolic syndrome features. Reflecting the underlying pathogenesis and the cardiometabolic disorders associated with NAFLD, the term metabolic (dysfunction)-associated fatty liver disease (MAFLD) has recently been proposed. Indeed, over the past few years, growing evidence supports a strong correlation between NAFLD and increased cardiovascular disease (CVD) risk, independent of the presence of diabetes, hypertension, and obesity. This implies that NAFLD may also be directly involved in the pathogenesis of CVD. Notably, liver sinusoidal endothelial cell (LSEC) dysfunction appears to be implicated in the progression of NAFLD via numerous mechanisms, including the regulation of the inflammatory process, hepatic stellate activation, augmented vascular resistance, and the distortion of microcirculation, resulting in the progression of NAFLD. Vice versa, the liver secretes inflammatory molecules that are considered pro-atherogenic and may contribute to vascular endothelial dysfunction, resulting in atherosclerosis and CVD. In this review, we provide current evidence supporting the role of endothelial cell dysfunction in the pathogenesis of NAFLD and NAFLD-associated atherosclerosis. Endothelial cells could thus represent a “golden target” for the development of new treatment strategies for NAFLD and its comorbid CVD.

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Section: Endothelial Cells In the Pathogenesis Of Nafldmentioning

confidence: 99%

Section: Endothelial Cells In the Pathogenesis Of Nafldmentioning

confidence: 99%

Section: Endothelial Cells In the Pathogenesis Of Nafldmentioning

confidence: 99%

Section: Endothelial Cells In the Pathogenesis Of Nafldmentioning

confidence: 99%

Section: Endothelial Cells In the Pathogenesis Of Nafldmentioning

confidence: 99%

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Endothelial Cell Dysfunction and Nonalcoholic Fatty Liver Disease (NAFLD): A Concise Review

Nasiri-Ansari

Ανδρουτσάκος

Flessa

et al. 2022

Cells

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Novel application of live imaging to determine the functional cell biology of endothelial-to-mesenchymal transition (EndMT) within a liver-on-a-chip platform

et al. 2022

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Objective Imaging endothelial cell behaviour under physiological conditions, particularly those associated with chronic fibrotic pathologies, is an incredibly challenging endeavour. While short-term assessments (hours) can be achieved with techniques such as intravital microscopy, vascular changes often occur over days and weeks which is unfeasible with current imaging techniques. These challenges are exemplified within the liver where liver sinusoidal endothelial cells (LSECs) are known to undergo dramatic changes termed endothelial-to-mesenchymal transition (EndMT) during fibrotic liver disease. Despite the established presence of EndMT in liver disease, the inaccessibility of viable liver tissue, and simplicity of 2D culture techniques has meant, the role of EndMT during disease progression remains largely undetermined. This study describes the development of novel fluorescent EndMT reporters to identify, track, and characterise the migratory behaviour of EndMT cells. We show that liver-on-a-chip (LOAC) platforms provide a flexible, optically accessible, and physiologically relevant microenvironment to study the vascular dynamics of EndMT during liver disease. Methods Identification, creation, and application of an EndMT-specific fluorescent reporter construct (EndMT-Rep). Transduction of EC using lentiviral packaged CNN1-eGFP construct as an inducible EndMT-Rep (CNN1-Rep) to 2D, 3D, and 4D imaging techniques for fixed and live cell imaging. Combined application of live and fixed imaging technologies to measure EndMT using CNN1-Rep on LOAC platform under physiological conditions. Demonstration of the high-resolution single-cell EndMT tracking by live cell time-lapse microscopy and with post-acquisition processing to perform a comparative study of CNN1-Rep and healthy LSECs within a NASH-like LOAC microenvironment. Conclusions LOAC enables prolonged, multi-platform imaging of endothelial cell sub-populations such as those undergoing EndMT in 2D and 3D cultures. Our study highlights the application of EndMT reporters, such as CNN1-Rep, to provide high-resolution imaging of EndMT behaviour for the first time under physiologically relevant liver microenvironment. Overall, these methods reveal the adaptability and impact of live-cell imaging on uncovering vascular behaviours, such as EndMT, that are unattainable in viable tissue or conventional 2D in vitro experiments.

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Loss of CEACAM1 in endothelial cells causes hepatic fibrosis

Muturi¹,

Ghadieh²,

Abdolahipour³

et al. 2023

Metabolism

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Gene Signatures Detect Damaged Liver Sinusoidal Endothelial Cells in Chronic Liver Diseases

Cited by 11 publications

References 67 publications

Endothelial Cell Dysfunction and Nonalcoholic Fatty Liver Disease (NAFLD): A Concise Review

Endothelial Cell Dysfunction and Nonalcoholic Fatty Liver Disease (NAFLD): A Concise Review

Novel application of live imaging to determine the functional cell biology of endothelial-to-mesenchymal transition (EndMT) within a liver-on-a-chip platform

Loss of CEACAM1 in endothelial cells causes hepatic fibrosis

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