Transforming growth factor‐β stimulates epithelial–mesenchymal transformation in the proepicardium

Olivey, Harold E.; Mundell, Nathan A.; Austin, Anita F.; Barnett, Joey V.

doi:10.1002/dvdy.20593

Cited by 72 publications

(59 citation statements)

References 52 publications

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“…In coculture experiments, TGF␤ has been implicated in the recruitment of smooth muscle cells by endothelial cells. 35,57 In vitro studies demonstrate that TGF␤ induces loss of epithelial character in both proepicardial 58 and epicardial cells 59 and smooth muscle differentiation in epicardial cells. 59 The loss of epithelial character and expression of smooth muscle marker proteins requires ALK5 kinase activity, implicating the canonical TGF␤ signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

Coronary Vessel Development Is Dependent on the Type III Transforming Growth Factor β Receptor

Compton

Potash

Brown

et al. 2007

Circulation Research

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113

132

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Abstract-Transforming growth factor (TGF)␤ receptor III (TGF␤R3), or ␤-glycan, binds all 3 TGF␤ ligands and inhibin with high affinity but lacks the serine/threonine kinase domain found in the type I and type II receptors (TGF␤R1, TGF␤R2). TGF␤R3 facilitates signaling via TGF␤R1/TGF␤R2 but also has been suggested to play a unique and nonredundant role in TGF␤ signaling. Targeted deletion of Tgfbr3 revealed a requirement for Tgfbr3 during development of the coronary vessels. Coronary vasculogenesis is significantly impaired in null mice, with few vessels evident and numerous, persistent blood islands found throughout the epicardium. Tgfbr3-null mice die at embryonic day 14.5, the time when functional coronary vasculature is required for embryo viability. However, in null mice nascent coronary vessels attach to the aorta, form 2 coronary ostia, and initiate smooth muscle recruitment by embryonic day 14. Analysis of earlier developmental stages revealed defects in the epicardium. At embryonic day 13.5, these defects include an irregular and hypercellular epicardium with abundant subepicardial mesenchyme and a thin compact zone myocardium. Tgfbr3-null mice also displayed other defects in coronary development, including dysmorphic and distended vessels along the atrioventricular groove and subepicardial hemorrhage. In null mice, vessels throughout the yolk sac and embryo form and recruit smooth muscle in a pattern indistinguishable from heterozygous or wild-type littermates. These data demonstrate a requirement for Tgfbr3 during coronary vessel development that is essential for embryonic viability. Key Words: coronary vessels Ⅲ transforming growth factor ␤ receptor Ⅲ mice, null C oronary artery disease is responsible for 54% of all cardiovascular disease in the United States. 1 Coronary vessels have a unique derivation from mesothelial cells that form a transitory structure termed the proepicardium. Proepicardial cells are transferred to the heart, form the epicardium, and give rise to endothelial cells, smooth muscle cells, and cardiac fibroblasts (reviewed elsewhere 2,3 ). Endothelial cells derived from the epicardium form a vascular plexus by the process of vasculogenesis. This vascular network attaches to the aorta and recruits epicardially derived mesenchyme to become vascular smooth muscle. The identification of the molecular and cellular processes that regulate coronary vessel development may provide insight into coronary vessel disease and reveal novel therapeutic opportunities.The transforming growth factor (TGF)␤ family of growth factors regulates cell growth and differentiation in the cardiovascular system during both development and disease. 4 -6 Three ligands, TGF␤1, TGF␤2, and TGF␤3, 7-9 bind 4 cell surface proteins. These include two transmembrane serine/ threonine kinase receptors, the type I TGF␤ receptor (TGF␤R1) and the type II TGF␤ receptor (TGF␤R2). 10 -12 Several type I receptors, termed activin receptor-like kinases (ALKs), have been described. TGF␤R2 has a constitutively active cytoplasmic...

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Section: Discussionmentioning

confidence: 99%

Coronary Vessel Development Is Dependent on the Type III Transforming Growth Factor β Receptor

Compton

Potash

Brown

et al. 2007

Circulation Research

Self Cite

113

132

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“…CFs are derived primarily from the proepicardial organ, a cluster of epithelial-like cells that migrate to cover the developing heart and form the mature epicardium. A substantial proportion of these cells undergo epithelial to mesenchymal transition (EMT) in response to TGF-β1 signaling to gain a more migratory, fibroblast-like phenotype before they invade the myocardium (Olivey et al, 2006). These cells are believed to be the origin of vascular smooth muscle cells, endothelial cells and resident cardiac fibroblasts.…”

Section: Cardiac Cell Responses To Mechanical Stressmentioning

confidence: 99%

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

Schroer

Merryman

2015

Journal of Cell Science

113

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Fibrotic cardiac disease, a leading cause of death worldwide, manifests as substantial loss of function following maladaptive tissue remodeling. Fibrosis can affect both the heart valves and the myocardium and is characterized by the activation of fibroblasts and accumulation of extracellular matrix. Valvular interstitial cells and cardiac fibroblasts, the cell types responsible for maintenance of cardiac extracellular matrix, are sensitive to changing mechanical environments, and their ability to sense and respond to mechanical forces determines both normal development and the progression of disease. Recent studies have uncovered specific adhesion proteins and mechano-sensitive signaling pathways that contribute to the progression of fibrosis. Integrins form adhesions with the extracellular matrix, and respond to changes in substrate stiffness and extracellular matrix composition. Cadherins mechanically link neighboring cells and are likely to contribute to fibrotic disease propagation. Finally, transition to the active myofibroblast phenotype leads to maladaptive tissue remodeling and enhanced mechanotransductive signaling, forming a positive feedback loop that contributes to heart failure. This Commentary summarizes recent findings on the role of mechanotransduction through integrins and cadherins to perpetuate mechanically induced differentiation and fibrosis in the context of cardiac disease.

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“…Fate mapping of the epicardium has demonstrated that it can give rise to cardiac fibroblasts and smooth muscle cells (Vrancken Peeters et al, 1999;Olivey et al, 2006;Acharya et al, 2011; Kikuchi et al, 2011;Acharya et al, 2012;Braitsch et al, 2012). Recent reports using the mouse model implied a role for Tcf21 in cell fate decisions, demonstrating a requirement for Tcf21 in the cardiac fibroblast lineage (Acharya et al, 2012;Braitsch et al, 2012).…”

Section: Tcf21 and Epicardial Cell Fatementioning

confidence: 99%

Tcf21 regulates the specification and maturation of proepicardial cells

Tandon

Miteva

et al. 2013

Development

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SUMMARYThe epicardium is a mesothelial cell layer essential for vertebrate heart development and pertinent for cardiac repair post-injury in the adult. The epicardium initially forms from a dynamic precursor structure, the proepicardial organ, from which cells migrate onto the heart surface. During the initial stage of epicardial development crucial epicardial-derived cell lineages are thought to be determined. Here, we define an essential requirement for transcription factor Tcf21 during early stages of epicardial development in Xenopus, and show that depletion of Tcf21 results in a disruption in proepicardial cell specification and failure to form a mature epithelial epicardium. Using a mass spectrometry-based approach we defined Tcf21 interactions and established its association with proteins that function as transcriptional co-repressors. Furthermore, using an in vivo systems-based approach, we identified a panel of previously unreported proepicardial precursor genes that are persistently expressed in the epicardial layer upon Tcf21 depletion, thereby confirming a primary role for Tcf21 in the correct determination of the proepicardial lineage. Collectively, these studies lead us to propose that Tcf21 functions as a transcriptional repressor to regulate proepicardial cell specification and the correct formation of a mature epithelial epicardium. KEY WORDS: Tcf21, Proepicardial organ, Heart developmentTcf21 regulates the specification and maturation of proepicardial cells ZnCl 2 , 1 μM CaCl 2 , 0.5% Triton X-100 (v/v), 150 mM NaCl, 4 μg/ml DNase, 1/100 (v/v) Protease Inhibitor Cocktail and 1/100 Phosphatase Inhibitor Cocktail] using 5 ml lysis buffer/g cell powder. Lysates were homogenized, subjected to centrifugation, and supernatants incubated for 1 hour with 7 mg magnetic beads (M270 Epoxy Dynabeads, Invitrogen) conjugated with anti-EGFP antibodies (Cristea et al., 2005). Proteins were eluted by incubation for 10 minutes (70°C) in 30 µl 1× LDS sample buffer (Invitrogen) containing 1× Reducing Agent (Invitrogen), followed by shaking at room temperature for 10 minutes. Panna In-solution digestion, mass spectrometry analysis and data processingProtein IP eluates were prepared as described Greco et al., 2011;Tsai et al., 2012). Briefly, IP eluates were mixed with 8 M urea in aqueous 0.1 M Tris-HCl pH 8.0, applied to ultrafiltration Vivacon 500 units (Sartorius Stedim), and centrifuged at 14,000 g for 40 minutes at 20°C. Samples were washed, alkylated and digested with trypsin (Promega) overnight at 37°C. Resulting peptides were collected by centrifugation, acidified with trifluoroacetic acid, concentrated by vacuum centrifugation, and desalted using Empore C18 StageTips (Rappsilber et al., 2007;. Peptides were analyzed by nLC-MS/MS using a Dionex Ultimate 3000 RSLC system coupled online to an LTQ-Orbitrap Velos mass spectrometer (ThermoFisher Scientific) Tsai et al., 2012). Peptides were fragmented by collisioninduced dissociation (CID) and the MS/MS spectra were extracted by Proteome Discoverer (ThermoFishe...

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Transforming growth factor‐β stimulates epithelial–mesenchymal transformation in the proepicardium

Cited by 72 publications

References 52 publications

Coronary Vessel Development Is Dependent on the Type III Transforming Growth Factor β Receptor

Coronary Vessel Development Is Dependent on the Type III Transforming Growth Factor β Receptor

Mechanobiology of myofibroblast adhesion in fibrotic cardiac disease

Tcf21 regulates the specification and maturation of proepicardial cells

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