scholarly journals MiR-126-3p Is Dynamically Regulated in Endothelial-to-Mesenchymal Transition during Fibrosis

2021 ◽  
Vol 22 (16) ◽  
pp. 8629
Author(s):  
Nina P. Jordan ◽  
Samuel J. Tingle ◽  
Victoria G. Shuttleworth ◽  
Katie Cooke ◽  
Rachael E. Redgrave ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Umbilical Vein ◽  
Cell Types ◽  
Heart Tissue ◽  
Lineage Tracing ◽  
Ischaemic Injury ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition ◽  
Over Expression ◽  
Endothelial To Mesenchymal Transition

In fibrotic diseases, myofibroblasts derive from a range of cell types including endothelial-to-mesenchymal transition (EndMT). Increasing evidence suggests that miRNAs are key regulators in biological processes but their profile is relatively understudied in EndMT. In human umbilical vein endothelial cells (HUVEC), EndMT was induced by treatment with TGFβ2 and IL1β. A significant decrease in endothelial markers such as VE-cadherin, CD31 and an increase in mesenchymal markers such as fibronectin were observed. In parallel, miRNA profiling showed that miR-126-3p was down-regulated in HUVECs undergoing EndMT and over-expression of miR-126-3p prevented EndMT, maintaining CD31 and repressing fibronectin expression. EndMT was investigated using lineage tracing with transgenic Cdh5-Cre-ERT2; Rosa26R-stop-YFP mice in two established models of fibrosis: cardiac ischaemic injury and kidney ureteric occlusion. In both cardiac and kidney fibrosis, lineage tracing showed a significant subpopulation of endothelial-derived cells expressed mesenchymal markers, indicating they had undergone EndMT. In addition, miR-126-3p was restricted to endothelial cells and down-regulated in murine fibrotic kidney and heart tissue. These findings were confirmed in patient kidney biopsies. MiR-126-3p expression is restricted to endothelial cells and is down-regulated during EndMT. Over-expression of miR-126-3p reduces EndMT, therefore, it could be considered for miRNA-based therapeutics in fibrotic organs.

scholarly journals Curcumin Blunts IL-6 Dependent Endothelial‐to‐Mesenchymal Transition to Alleviate Renal Allograft Fibrosis Through Autophagy Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Jiajun Zhou ◽  
Mengtian Yao ◽  
Minghui Zhu ◽  
Mengchao Li ◽  
Qiwei Ke ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Kidney Transplantation ◽  
Renal Allograft ◽  
Umbilical Vein ◽  
Rat Kidney ◽  
Graft Loss ◽  
Cell Types ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

Fibrosis contributes to graft loss in chronic renal allograft injury. Endothelial‐to‐mesenchymal transition (EndMT) plays an important role in the development of fibrosis following kidney transplantation. Autophagy plays an important role in the homeostasis of diverse cell types including endothelial cells. Here we demonstrate that inhibition of autophagy by treatment with 3-methyladenine (3-MA) or by silencing autophagy-related (ATG)5 promoted interleukin (IL)-6–dependent EndMT in human umbilical vein endothelial cells (HUVECs) and human renal glomerular endothelial cells (HRGECs), and autophagy inactivation was associated with EndMT in patients with chronic allograft dysfunction. IL-6 level was significantly higher in the culture medium of HUVECs transfected with ATG5 siRNA or treated with 3-MA compared to the respective control groups. IL-6 application induced EndMT in HUVECs and HRGECs, whereas antibody-mediated neutralization of IL-6 suppressed EndMT induced by ATG5 silencing. The protective role of curcumin (Cur) against allograft fibrosis was confirmed in a rat kidney transplantation model of F344 donors to Lewis recipients. Curcumin—a natural polyphenol compound with known antifibrotic effects in various tissues—alleviated IL-6–induced EndMT and promoted autophagy in the allografted organ and in HUVECs. This is the first demonstration of the role of autophagy in renal allograft fibrosis; our findings indicate that curcumin can alleviate chronic renal allograft injury by suppressing IL-6–dependent EndMT via activation of autophagy.

scholarly journals Endothelial Cells Tissue-Specific Origins Affects Their Responsiveness to TGF-β2 during Endothelial-to-Mesenchymal Transition

2019 ◽  
Vol 20 (3) ◽  
pp. 458 ◽  
Author(s):  
Fernanda Ursoli Ferreira ◽  
Lucas Eduardo Botelho Souza ◽  
Carolina Hassibe Thomé ◽  
Mariana Tomazini Pinto ◽  
Clarice Origassa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Umbilical Vein ◽  
Transforming Growth Factor Β ◽  
Selective Inhibition ◽  
Mesenchymal Transition ◽  
Best Response ◽  
Endothelial To Mesenchymal Transition

The endothelial-to-mesenchymal transition (EndMT) is a biological process where endothelial cells (ECs) acquire a fibroblastic phenotype after concomitant loss of the apical-basal polarity and intercellular junction proteins. This process is critical to embryonic development and is involved in diseases such as fibrosis and tumor progression. The signaling pathway of the transforming growth factor β (TGF-β) is an important molecular route responsible for EndMT activation. However, it is unclear whether the anatomic location of endothelial cells influences the activation of molecular pathways responsible for EndMT induction. Our study investigated the molecular mechanisms and signaling pathways involved in EndMT induced by TGF-β2 in macrovascular ECs obtained from different sources. For this purpose, we used four types of endothelial cells (coronary artery endothelial cells, CAECs; primary aortic endothelial cells PAECs; human umbilical vein endothelia cells, HUVECs; and human pulmonary artery endothelial cells, HPAECs) and stimulated with 10 ng/mL of TGF-β2. We observed that among the ECs analyzed in this study, PAECs showed the best response to the TGF-β2 treatment, displaying phenotypic changes such as loss of endothelial marker and acquisition of mesenchymal markers, which are consistent with the EndMT activation. Moreover, the PAECs phenotypic transition was probably triggered by the extracellular signal–regulated kinases 1/2 (ERK1/2) signaling pathway activation. Therefore, the anatomical origin of ECs influences their ability to undergo EndMT and the selective inhibition of the ERK pathway may suppress or reverse the progression of diseases caused or aggravated by the involvement EndMT activation.

scholarly journals Endothelial-to-Mesenchymal Transition (EndoMT): Roles in Tumorigenesis, Metastatic Extravasation and Therapy Resistance

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Valentin Platel ◽  
Sébastien Faure ◽  
Isabelle Corre ◽  
Nicolas Clere
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Cell Types ◽  
Therapy Resistance ◽  
Experimental Conditions ◽  
Potential Implication ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

Cancer cells evolve in a very complex tumor microenvironment, composed of several cell types, among which the endothelial cells are the major actors of the tumor angiogenesis. Today, these cells are also characterized for their plasticity, as endothelial cells have demonstrated their potential to modify their phenotype to differentiate into mesenchymal cells through the endothelial-to-mesenchymal transition (EndoMT). This cellular plasticity is mediated by various stimuli including transforming growth factor-β (TGF-β) and is modulated dependently of experimental conditions. Recently, emerging evidences have shown that EndoMT is involved in the development and dissemination of cancer and also in cancer cell to escape from therapeutic treatment. In this review, we summarize current updates on EndoMT and its main induction pathways. In addition, we discuss the role of EndoMT in tumorigenesis, metastasis, and its potential implication in cancer therapy resistance.

scholarly journals Liraglutide Inhibits Endothelial-to-Mesenchymal Transition and Attenuates Neointima Formation after Endovascular Injury in Streptozotocin-Induced Diabetic Mice

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 589 ◽  
Author(s):  
Tzu-Hsien Tsai ◽  
Chien-Ho Lee ◽  
Cheng-I Cheng ◽  
Yen-Nan Fang ◽  
Sheng-Ying Chung ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Morphological Changes ◽  
Umbilical Vein ◽  
Vascular Complications ◽  
Specific Marker ◽  
Neointima Formation ◽  
Diabetic Mice ◽  
Mesenchymal Transition ◽  
Compound C ◽  
Endothelial To Mesenchymal Transition

Hyperglycaemia causes endothelial dysfunction, which is the initial process in the development of diabetic vascular complications. Upon injury, endothelial cells undergo an endothelial-to-mesenchymal transition (EndMT), lose their specific marker, and gain mesenchymal phenotypes. This study investigated the effect of liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, on EndMT inhibition and neointima formation in diabetic mice induced by streptozotocin. The diabetic mice with a wire-induced vascular injury in the right carotid artery were treated with or without liraglutide for four weeks. The degree of neointima formation and re-endothelialisation was evaluated by histological assessments. Endothelial fate tracing revealed that endothelium-derived cells contribute to neointima formation through EndMT in vivo. In the diabetic mouse model, liraglutide attenuated wire injury-induced neointima formation and accelerated re-endothelialisation. In vitro, a high glucose condition (30 mmol/L) triggered morphological changes and mesenchymal marker expression in human umbilical vein endothelial cells (HUVECs), which were attenuated by liraglutide or Activin receptor-like 5 (ALK5) inhibitor SB431542. The inhibition of AMP-activated protein kinase (AMPK) signaling by Compound C diminished the liraglutide-mediated inhibitory effect on EndMT. Collectively, liraglutide was found to attenuate neointima formation in diabetic mice partially through EndMT inhibition, extending the potential therapeutic role of liraglutide.

scholarly journals Advanced Glycation End Products Induce Endothelial-to-Mesenchymal Transition via Downregulating Sirt 1 and Upregulating TGF-βin Human Endothelial Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Wei He ◽  
Jian Zhang ◽  
Tian-yi Gan ◽  
Guo-jun Xu ◽  
Bao-peng Tang
Keyword(s):  
Endothelial Cells ◽  
Advanced Glycation End Products ◽  
Umbilical Vein ◽  
Advanced Glycation ◽  
Mesenchymal Transition ◽  
Smooth Muscle Antibody ◽  
Protein Levels ◽  
Glycation End Products ◽  
End Products ◽  
Endothelial To Mesenchymal Transition

In the present study, we examined the advanced glycation end products- (AGEs-) induced endothelial-to-mesenchymal transition (EndMT) in human umbilical vein endothelial cells (HUVECs). Results demonstrated that AGE-BSAs significantly reduced the cluster of differentiation 31 (CD 31) expression, whereas they promoted the expression of fibroblast-specific protein-1 (FSP-1),α-smooth muscle antibody (α-SMA), and collagen I at both mRNA and protein levels in HUVECs. And the AGE-BSAs also promoted the receptors for AGEs (RAGEs) and receptor I for TGF-β(TGFR I) markedly with a dose dependence, whereas the Sirt 1 was significantly downregulated by the AGE-BSA at both mRNA and protein levels. Moreover, the Sirt 1 activity manipulation with its activator, resveratrol (RSV), or its inhibitor, EX527, markedly inhibited or ameliorated the AGE-mediated TGF-βupregulation. And the manipulated Sirt 1 activity positively regulated the AGE-induced CD31, whereas it negatively regulated the AGE-induced FSP-1. Thus, Sirt 1 was confirmed to regulate the AGE-induced EndMT via TGF-β. In summary, we found that AGE-BSA induced EndMT in HUVECs via upregulating TGF-βand downregulating Sirt 1, which also negatively regulated TGF-βin the cell. This study implied the EndMT probably as an important mechanism of AGE-induced cardiovascular injury.

Abstract 369: Isolation and Characterization of Developmentally and Functionally Discrete Subsets of Cardiac Fibroblasts

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Reza Ardehali ◽  
Shah Ali ◽  
Irving Weissman
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Cardiac Fibroblasts ◽  
Cell Types ◽  
Lineage Tracing ◽  
Reporter Protein ◽  
Hematopoietic Stem ◽  
Mesenchymal Transition ◽  
Isolation And Characterization ◽  
Embryonic Origin

Although cardiac fibroblasts (CF) are the most prominent cell types in the heart, little is known about their origin and development. Fibroblasts play a key role in regulating the normal myocardial function, as well as the adverse remodeling that occurs with injury. Fundamental to understanding cardiac development is the ability to determine when and where CFs are generated, their ancestry, and how they move to reside in their final position. We used novel transgenic mouse models to lineage trace the developmental origin of CFs and their contribution to fibrosis in response to injury. Here, we show that a subset of cardiac fibroblasts is derived from Mesp1-expressing cells (multipotent cardiac progenitor cells that contribute to precursors of both heart fields). Using Mesp1-Cre;mT/mG mice, in which cells derived from Mesp1-expressing cells are indelibly marked by the GFP reporter protein, we demonstrate that approximately 65% of CFs share an embryonic origin with cardiomyocytes, vascular smooth muscle, and endothelial cells. In addition, experimental myocardial fibrosis did change this proportion. In an attempt to identify the source of the fibroblasts that are non-MesP1-derived, we evaluated contribution from: (i) the bone marrow stromal cells and hematopoietic stem cells, (ii) endothelial-to-mesenchymal transition, (iii) circulating cells, and (iv) epicardial-derived cells. Transplantation of GFP-bone marrow into irradiated wildtype mice resulted in an insignificant contribution of stromal-derived fibroblasts in the heart in response to injury. Using Tie2-Cre;mT/mG mice, we did not observe cardiac fibroblasts originating from endothelial cells in injured hearts. Finally, using a parabiotic pair of GFP and wildtype mice where blood chimerism is established, no evidence for homing of circulating fibroblasts to the heart upon injury was noted. However, we provide unequivocal evidence that epicardial-derived cells migrate to myocardium as fibroblasts to contribute to fibrosis. In summary, using lineage-tracing systems, we provide evidence for two sources of fibroblasts in the heart, one that shares an embryonic origin with the cardiovascular lineages and the other from a non-cardiac origin, which is primarily derived from the epicardium.

scholarly journals LARP7 Suppresses Endothelial-to-Mesenchymal Transition by Coupling with TRIM28

2021 ◽  
Author(s):  
Xiaodong Liang ◽  
Shuo Wu ◽  
Zilong Geng ◽  
Li Liu ◽  
Shasha Zhang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Rna Polymerase Ii ◽  
Transforming Growth Factor Beta ◽  
Rna Binding ◽  
Transforming Growth Factor ◽  
Lineage Tracing ◽  
Epigenetic Mechanism ◽  
Double Knockout ◽  
Mesenchymal Transition ◽  
Endothelial To Mesenchymal Transition

Rationale: Endothelial-to-mesenchymal transition (EndMT) is a fundamental biological process in which endothelial cells lose their endothelial characteristics and acquire mesenchymal properties. EndMT contributes to physiological organ development such as valvulogenesis, and is associated with a number of deleterious pathologies such as organ fibrosis. Several signaling pathways of transforming growth factor beta (TGF-β), bone morphogenetic protein (BMP) and inflammation have been shown to regulate EndMT. However, the transcriptional and epigenetic programs governing EndMT remains largely unclarified. Objective: To identify the transcriptional or epigenetic mechanisms underlying EndMT and EndMT-associated formation of cardiac valves. Methods and Results: We identified the La ribonucleoprotein domain family member 7 (LARP7), a RNA binding protein regulating RNA polymerase II (RNAPII) pausing, was downregulated in two cytokine-induced EndMT models. LARP7 depletion with lentivirus-mediated shRNA transformed endothelial cells to mesenchymal morphology and induced the expression of the EndMT key regulator, SLUG. Specific deletion of LARP7 in the endocardium in inducible CDH5CreERT2;LARP7f/f mouse enhanced EndMT in the atrioventricular and outflow tract (OFT) cushion as revealed by lineage tracing approach. ChIP-seq analysis showed LARP7 and Tripartite Motif Containing 28 (TRIM28) which is an epigenetic repressor were colocalized at SLUG promoter. LARP7 directly interacted with TRIM28 and facilitated it loading to SLUG promoter and repressed its transcription through deacetylating the histones. More importantly, inducible knockout of LARP7 or TRIM28 in the endocardium accelerated EndMT, leading to the valvular hyperplasia, which was further aggravated by the double knockout of these two genes. Conclusions: The present study uncovers an orchestrated transcriptional and epigenetic mechanism by which LARP7 cooperates with TRIM28 to govern the EndMT and valvulogenesis.

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