Transcription Factor 4 Maintains Endothelial Cell Identity by Inhibiting Endothelial to Mesenchymal Transition
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE242102 | GEO | 2025/12/03
REPOSITORIES: GEO
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Project description:Endothelial-to-mesenchymal transition (EndoMT) is essential for embryonic heart development and contributes to many disease-causal pathobiological processes. It is unclear how the balance between endothelial cell (EC) identity and EndoMT mediators is regulated to drive this transition. This study identifies TCF4 as a critical EC identity gene. TCF4 knockdown in ECs impairs EC phenotype and function, and induces EC identity transition towards mesenchymal-like state. This discovery suggests that TCF4 functions as a guardian of EC identity against EndoMT. Mechanistically, TCF4 binds directly to the promoter of TGFB1 and SNAI1, leading to the repression of their expression. TCF4 expression is consistently downregulated in three EndoMT models. TCF4 downregulation diminishes its inhibitory effect on the TGFB signaling pathway, leading to upregulation of SNAI1 and TGFB1, and subsequently enhancing EndoMT. This, in turn, further suppresses TCF4 expression. Consequently, the TCF4-TGFB1 feedback loop is formed to intensify the EndoMT process. We demonstrate that introducing exogenous TCF4 disrupts this TCF4-TGFB1 feedback loop of EndoMT, rescuing EC phenotype and function under TGFB1 stimulation, as well as ECs from heart failure patients. Our results reveal a key role of TCF4 in safeguarding EC identity and preventing EndoMT, suggesting a therapeutic potential of TCF4 for EndoMT-related cardiovascular diseases.
2025-12-03 | GSE302125 | GEO
Project description:Conflicting reports exist on whether endothelial cells (ECs) serve as a source of bone marrow stromal cells (BMSCs). In studies concerning the endothelial-to-mesenchymal transition (EndoMT), ECs expressing mesenchymal markers, as well as BMSCs expressing endothelial markers, are typically considered intermediates of EndoMT. To understand the lineage relationship between ECs and BMSCs in postnatal mouse bone marrow, we performed single-cell RNA sequencing (scRNA-seq) on ECs and BMSCs obtained from 5-week-old wild-type C57BL/6J mice, and analyzed the potential intermediates of EndoMT. Subsequently, BMSC and EC lineage tracing models, flow cytometry, and immunostaining techniques were used to validate the findings from scRNA-seq analysis.
2023-11-24 | GSE168333 | GEO
Project description:Vascular networks form, remodel and mature under the influence of both fluid shear stress (FSS) and soluble factors. Physiological FSS promotes and maintains vascular stability via synergy with Bone Morphogenic Protein 9 (BMP9) and BMP10. Conversely, mutation of the BMP receptors ALK1, Endoglin or the downstream effector SMAD4 leads to Hereditary Hemorrhagic Telangiectasia (HHT), characterized by fragile and leaky arterial-venous malformations (AVMs). But how endothelial cells (EC) integrate FSS and BMP signals in vascular development and homeostasis, and how mutations give rise to vascular malformations is not well understood. Here, we aimed to elucidate the mechanism of synergy between fluid shear stress and SMAD signaling in vascular stability and its failure in HHT. We have now found that loss of Smad4 increases ECs’ sensitivity to flow by lowering the FSS set point with resulting AVMs exhibiting features of excessive flow-mediated morphological responses. Mechanistically, loss of Smad4 disinhibits flow-mediated Klf4-Tie2-PI3K/Akt signaling leading to increased EC proliferation and loss of arterial identity due to Klf4-mediated repression of cyclin dependent Kinase (CDK) inhibitors, CDKN2A and CDKN2B. Thus, AVMs caused by Smad4 deletion are characterized by chronic high flow remodeling with excessive EC proliferation and loss of arterial identity as triggering events.
2023-07-03 | GSE232443 | GEO
Project description:Background: A comprehensive understanding of the determinants of endothelial cell (EC) lineage specification will advance strategies for cardiovascular regenerative medicine. Recent studies found that unique epigenetic signatures specifically regulate cell identity genes, making it possible to systematically identify novel EC master regulators by leveraging extensive epigenomic datasets available for EC. Methods: We developed a method to identify novel regulators of endothelial cell identity by integrating multiple epigenetic patterns. We verified MEOCM as a master EC lineage regulator using both in vivo and in vitro experiments. The mechanism of action of MECOM as EC lineage regulator was characterized by integrative analysis of Hi-C, DNase-Seq, ChIP-Seq, scRNA-seq and bulk RNA-Seq data, as well as extensive molecular, cellular, and animal experiments. Results: We identified MECOM to be the leading candidate as an EC lineage regulator. Single-cell RNA-Seq analysis further revealed that MECOM-positive cells are exclusively enriched in the cell cluster of bona fide iPSC-ECs. We verified that MECOM was required for human endothelial differentiation, EC functions, and Zebrafish angiogenesis. Through integrative analysis of Hi-C, DNase-Seq, ChIP-Seq, and RNA-Seq data, we find MECOM binds enhancers that form chromatin loops to regulate EC identity genes. Specifically, we identified the VEGF signaling pathway to be a key downstream target of MECOM. Conclusions: Our work provides new insights into epigenetic regulation of cell identity genes and uncovered MECOM as a master regulator of EC identity.
2023-03-16 | GSE160647 | GEO
Project description:Proliferation of vascular endothelial cells (ECs) is critical for providing sufficient cells lining the neo-vascular lumen. Moreover, expanding ECs need to undergo multiple steps to line new lumen, functionalizing anti-thrombotic and anti-inflammatory interface that prevents extravasation of inflammatory cells, maintains blood perfusion, and facilitates cellular crosstalk. Therefore, productive angiogenesis in regeneration requires formation of endothelial tight junction, arrangement of endothelial apical lumen, and alignment of basolateral side juxtaposed with alveolar epithelial cells. As a result, we used single cell RNA sequencing (scRNA-seq) to detect the function of diverse EC clusters.
2025-08-01 | GSE275285 | GEO
Project description:Endothelial cell (EC)-enriched protein coding genes, such as endothelial nitric oxide synthase (eNOS), define quintessential EC-specific physiologic functions. It is not clear whether long noncoding RNAs (lncRNAs) also define cardiovascular cell-type specific phenotypes, especially in the vascular endothelium. Here, we report the existence of a set of EC-enriched lncRNAs and define a role for STEEL (spliced transcript – endothelial enriched lncRNA) in angiogenic potential, macrovascular/microvascular identity and shear stress responsiveness. STEEL is expressed from the terminus of the HOXD locus and is transcribed antisense to HOXD transcription factors. STEEL RNA increases the number and integrity of de novo perfused microvessels in an in vivo model and augments angiogenesis in vitro. The STEEL RNA is polyadenylated, nuclear-enriched and has microvascular predominance. Functionally, STEEL regulates a number of genes in diverse endothelial cells. Of interest, STEEL upregulates both eNOS and the transcription factor Kruppel-like factor 2 (KLF2), and is subject to feedback inhibition by both eNOS and shear-augmented KLF2. Mechanistically, STEEL upregulation of eNOS and KLF2 is transcriptionally mediated, in part, via interaction of chromatin-associated STEEL with the poly-ADP ribosylase, PARP1. For instance, STEEL recruits PARP1 to the KLF2 promoter. This work identifies a role for EC-enriched lncRNAs in the phenotypic adaptation of ECs to both body position and hemodynamic forces, and establishes a newer role for lncRNAs in the transcriptional regulation of EC identity.
2018-02-28 | PXD008581 | Pride
Project description:Type I interferon (IFN-1) signatures are a hallmark of patients with systemic sclerosis (SSc). However, its significance in clinical stratification and contribution to deterioration still need to be better understood. For hypothesis generation, we performed single-cell RNA sequencing (scRNAseq) on skin biopsies (SSc=4, control =2) using the BD Rhapsody platform. The IFN-1 signature was mapped, functionally investigated in a bleomycin plus IFNα2-adeno-associated virus (IFNA2-AAV) induced model, and verified in an SSc cohort (n=61). Endothelial cells (EC) had the most prominent IFN-1 signature among dermal non-immune cells. The EC IFN-1 signature was increased both in SSc vs. controls and in dcSSc vs. lcSSc. IFNA2-AAV deteriorated bleomycin-induced dermal fibrosis, EndoMT, and perivascular fibrosis and caused blood vessel loss with EC apoptosis. Vascular MX1, an IFN-1 response protein, was significantly increased both in total SSc skin vs. healthy controls and in dcSSc vs. lcSSc. Baseline vascular MX1 performed similarly to skin score in predicting disease progression over 6-34 months in total SSc and was superior in the dcSSc subpopulation. To sum up, the EC IFN-1 signature distinguished SSc skin subtypes and disease progression and may contribute to vasculopathy and fibrosis.
2025-03-31 | GSE236111 | GEO
Project description:Abstract: Although Kawasaki disease (KD) and Multisystem inflammatory syndrome in children (MIS-C) share some clinical manifestations, their cardiovascular outcomes are different, and this may be reflected at the level of the endothelial cell (EC). We performed RNA-seq on cultured ECs incubated with pre-treatment sera from KD (n=5), MIS-C (n=7), and healthy controls (n=3). We conducted Weighted Gene Co-expression Network Analysis (WGCNA) using 935 transcripts differentially expressed between MIS-C and KD using soft filtering (un-adjusted p<0.05, >1.1 fold difference). We found seven gene modules annotated as increased TNFα/NFB pathway, decreased Endothelial-Mesenchymal Transition (EndoMT) and EC homeostasis, an-ti-inflammation and immune response, translation, and glucocorticoid responsive gene suppression in MIS-C. To further understand the difference in the EC response between KD and MIS-C, a hard filter was applied to identify 41 differentially expressed genes (DEGs) between KD and MIS-C (adjusted p<0.05, >2 fold-difference). Again, the majority was NFB pathway genes including nine upregulated pro-survival genes. Expression levels were higher in the genes influencing autophagy (UBD, EBI3, and SQSTM1). Other DEGs also supported the finding by WGCNA. Compared to KD, ECs in MIS-C had increased pro-survival transcripts, but reduced transcripts related to EndoMT and EC homeostasis. These differences in EC response may in-fluence the different cardiovascular outcomes in these two diseases.
2023-08-21 | GSE236833 | GEO
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