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Multiomic profiling of in vitro models of endothelial-to-mesenchymal transition reveals endothelial cell subtype is a major determinant of fidelity to observed states in atherosclerosis

ABSTRACT: Endothelial-to-mesenchymal transition (EndMT) is an example of endothelial cell (EC) heterogeneity which is commonly modeled in vitro to better understand driving mechanisms of disease proceses, including atherosclerosis. We used multi-modal single nucleus RNA sequencing (snRNA-seq) and ATAC sequencing (snATAC-seq) to analyze the diversity of ECs in vitro, divergent EC responses to known EndMT perturbations, and the ability of in vitro EC known EndMT models to recapitulate the in vivo 'omic profiles of cells observed in atherosclerosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228428 | GEO | 2023/05/03

REPOSITORIES: GEO

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Long non-coding RNA MIR503HG controls endothelial-to-mesenchymal transition

Project description:Endothelial-to-mesenchymal transition (EndMT) is a dynamic transformation process that has a functional impact upon pathological vascular remodelling. The molecular mechanisms that govern EndMT remain largely unknown. By induction of EndMT in human primary endothelial cells (EC), using a combination of transforming growth factor-β2 (TGF-b2) and interleukin-1b (IL-1β), we identified the dramatic loss of the lncRNA MIR503HG, as a common signature across multiple primary EC types. Targeted depletion of MIR503HG spontaneously induced EndMT. Overexpression of MIR503HG repressed EndMT despite TGF-β2 and IL-1β co-stimulation. RNA-seq was carried out to identify the changes in gene expression induced by MIR503HG overexpression. We showed that over 25% of the EndMT-transcriptome signature was inhibited upon MIR503HG overexpression. Crucially, phenotypic changes induced by MIR503HG were independent of the functional regulation of miR-503 and miR-424, both harbored within the MIR503HG locus. Collectively, we identify the lncRNA MIR503HG as an essential regulator of EndMT.

2020-12-31 | GSE118815 | GEO

ARPCs Can Revert Lps-Induced Endothelial-to-Mesenchymal Transition of Endothelial Cells

Project description:Endothelial dysfunction is a hallmark of LPS-induced acute kidney injury (AKI). Endothelial cells (EC) acquired a fibroblast-like phenotype and contributed to myofibroblasts generation through Endothelial to Mesenchymal Transition (EndMT) process. Noteworthy, ARPCs enhance tubular regenerative mechanism during AKI, but little is known about their effects on EC. Here we investigated whether ARPCs could prevent sepsis-induced EndMT and the related mechanism. When activated by LPS, Human endothelial cells (EC) proliferated and decreased specific EC markers such as CD31 and VE-cadherin and up-regulated myofibroblast markers such as Collagen I and Vimentin. The co-culture with ARPCs normalized EC proliferation rate and abrogated the LPS-induced EndMT by restoring the high expression of EC markers and the low expression of myofibroblast markers. Gene set enrichment analysis showed that most of genes modulated in LPS-stimulated ARPCs belongs to cell activation and defense response pathways. In particular, among most up-regulated genes we found BPIFA2, SAA2, SAA4 and CXCL6. BPIFA2 is recently described as an early biomarker of AKI but little is known about its function in the kidney. The other genes are frequently involved in the response to bacterial infection and kidney injury. Finally, in a swine model of LPS-induced AKI, we observed an increase of CD133+ARPCs that expressed BPIFA2 respect to healthy pigs. Taken together, these results suggest an underestimate role of ARPCS in preventing endothelial dysfuncton by the production of several proteins. The identification of these molecules may offer novel strategies to protect endothelial compartment and promote kidney repair.

2019-07-01 | GSE116849 | GEO

Progerin Expression in Endothelial Cells Induces Endothelial Dysfunction

Project description:Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, genetic premature aging disorder associated with severe atherosclerosis, often resulting in fatal heart attacks and strokes. Progerin, the mutant protein in HGPS, also is expressed in healthy individuals and may play a role in the development of atherosclerosis during physiologic aging. Here, we provide evidence for a primary involvement of vascular endothelium in the pathogenesis of accelerated atherosclerosis in HGPS. Expression of progerin in cultured human endothelial cells induces a dysfunctional phenotype, manifested by activation of multiple pro-inflammatory, pro-atherogenic genes. In particular, our data implicate endothelial-derived interleukin-1 (IL-1) as a key mediator of a pro-inflammatory vascular phenotype. Endothelial activation also is detectable in a mouse model of HGPS, and appears to be conveyed to neighboring vascular cells via autocrine and paracrine signaling. These new mechanistic insights into the vascular pathobiology of HGPS may have therapeutic implications for this disease. Genome-wide transcriptional profiling was carried out to assess functional phenotypic changes in endothelial cells (EC) as a result of progerin expression. Cultured EC were infected with an adenovirus expressing progerin (Ad-Progerin), and as a control, an adenovirus that did not express any construct (Ad-Null). Experiments were preformed with three different EC cultures.

2010-12-02 | E-GEOD-19270 | biostudies-arrayexpress

Single cell RNA-seq analysis of endothelial cells (HUVEC) treated with IL1b and TGFb2 as a model of endothelial to mesenchymal transition (EndMT)

Project description:Endothelial-to-mesenchymal transition (EndMT) is a dynamic biological process involved in pathological vascular remodeling. However, the molecular mechanisms that govern this transition remain largely unknown. To study EndMT in vitro, human umbilical vein endothelial cells (HUVEC) were treated with transforming growth factor-β2 and interleukin-1β, leading to a decrease of endothelial markers as well as an increase of mesenchymal markers and EndMT regulators after 7 days. Single-cell RNA-seq was carried out to study the dynamics of the transition.

2021-04-06 | GSE159843 | GEO

Endothelial Cells from different anatomical origin have distinct responses during Snail/TGF-β2-mediated Endothelial-Mesenchymal Transition

Project description:Endothelial-mesenchymal transition (EndMT) is a complex process, in which differentiated endothelial cells undergo phenotypic transition to mesenchymal cells. Given the diversity of the vascular system in architecture, structure, and embryonic origins, it is not clear if endothelial cells lining different vessels are able to undergo EndMT. Therefore, the aim of this study was to evaluate the molecular and functional changes that occur in different types of endothelial cells after induction of EndMT through overexpression of Snail and TGF-β2. Different types of endothelial cells (human umbilical vein, heart, and lung) have distinct response when induced to undergo EndMT. Coronary artery endothelial cells (HCAEC) induced with combined Snail overexpression plus TGF-β2 treatment promotes a decrease of endothelial markers, an increase of mesenchymal markers and migration. The mechanism that HCAEC undergoing EndMT may be mediated through Notch and non-canonical Wnt signaling pathways. These results provide the foundation for understanding the roles of specific signaling pathways in mediating EndMT in endothelial cells from different anatomical origin.

2017-04-22 | GSE96089 | GEO

MiRNA profiling in aortas of Apoe-/- mice with an specific knock-out of Dicer in endothelial cells compared to control mice after 12 weeks of a high-fat diet

Project description:Increased monocyte adhesion to dysfunctional endothelial cells (ECs) orchestrated by chemokines plays an important role in arterial inflammation during atherosclerosis. Endothelial microRNAs (miRNAs) processed by the RNase Dicer1 determine the phenotype of ECs by posttranscriptional regulation of gene expression. However, the impact of endothelial miRNAs on endothelial inflammation and atherosclerosis is currently unclear. To study the effect of Dicer-dependent miRNAs in ECs on atherosclerosis, Apoe-/- mice with an inducible, EC-specific knock-out of Dicer (EC-Dicerflox) and control mice (EC-DicerWT) mice were treated with tamoxifen to induce Cre-recombinase activity and fed with a high fat-diet (HFD) for 12 weeks. The comparison of the miRNA expression profile in the aortas of EC-Dicerflox and EC-DicerWT mice after 12 weeks of a HFD was performed to identify EC-specific miRNAs that may play a role in the EC function during atherogenesis.

2015-05-31 | GSE53433 | GEO

MiRNA expression profile in the aortas of Apoe-/- mice with an specific knock-out of Dicer in endothelial cells compared to control mice after 4 weeks of a high-fat diet

Project description:Increased monocyte adhesion to dysfunctional endothelial cells (ECs) orchestrated by chemokines plays an important role in arterial inflammation during atherosclerosis. Endothelial microRNAs (miRNAs) processed by the RNase Dicer1 determine the phenotype of ECs by posttranscriptional regulation of gene expression. However, the impact of endothelial miRNAs on endothelial inflammation and atherosclerosis is currently unclear. To study the effect of Dicer-dependent miRNAs in ECs during the development of atherosclerosis, Apoe-/- mice with an inducible, EC-specific knock-out of Dicer (EC-Dicerflox) and control mice (EC-DicerWT) mice were treated with tamoxifen to induce Cre-recombinase activity and fed with a high fat-diet (HFD) for 4 weeks. The comparison of the miRNA expression profile in the aortas of EC-Dicerflox and EC-DicerWT mice after 4 weeks of a HFD was performed to identify EC-specific miRNAs that may play a role in the EC function during atherogenesis.

2015-05-31 | GSE53435 | GEO

The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition [microarray]

Project description:Endothelial cells play an important role in maintenance of the vascular system and the repair after injury. Under pro-inflammatory conditions, endothelial cells can acquire a mesenchymal phenotype by a process named endothelial-to-mesenchymal transition (EndMT), which affects the functional properties of endothelial cells. Here, we investigated the epigenetic control of EndMT. We show that the histone demethylase JMJD2B is induced by EndMT promoting pro-inflammatory and hypoxic conditions. Silencing of JMJD2B reduced TGF-β2-induced expression of mesenchymal genes and prevented the alterations in endothelial morphology and impaired endothelial barrier function. Endothelial-specific deletion of JMJD2B in vivo confirmed a reduction of EndMT after myocardial infarction. EndMT did not affect global H3K9me3 levels but induced a site-specific reduction of repressive H3K9me3 marks at promoters of mesenchymal genes, such as Calponin (CNN1), and genes involved in TGF-β signaling, such as AKT Serine/Threonine Kinase 3 (AKT3) and sulfatase 1 (SULF1). Silencing of JMJD2B prevented the EndMT-induced reduction of H3K9me3 marks at these promotors and further repressed these EndMT-related genes. Our study reveals that endothelial identity and function is critically controlled by the histone demethylase JMJD2B, which is induced by EndMT-promoting pro-inflammatory and hypoxic conditions and support the acquirement of a mesenchymal phenotype.

2020-01-08 | GSE143150 | GEO

The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition [HTS]

2020-01-08 | GSE143148 | GEO

LARP7 suppresses endothelial-to-mesenchymal transition by coupling with TRIM28

Project description:LARP7 plays a pivotal role in regulating endothelial-to-mesenchymal transition(EndMT) and EndMT-associated heart valve formation. LARP7 directly interactes with TRIM28 and cooperatively represses SLUG transcription, which thereby suppresses EndMT of endothelial cells. More importantly, inducible knockout of LARP7 or TRIM28 in the endocardium promotes EndMT in vivo and leads to the valvular hyperplasia.

2023-09-22 | GSE165400 | GEO

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