BMP Signals Promote Proepicardial Protrusion Necessary for Recruitment of Coronary Vessel and Epicardial Progenitors to the Heart

Ishíi, Yasuo; Garriock, Robert J.; Navetta, A; Coughlin, Laura; Matsukawa, Takashi

doi:10.1016/j.devcel.2010.07.017

Cited by 80 publications

(101 citation statements)

References 78 publications

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“…30 Increased Bmpdependent signaling in RBPJk mutants was deduced on the basis of higher nuclear p-Smad 1/5/8 expression in the proepicardium and associated PM, and indicated that Bmp2 activity was expanded to the entire inflow region. Ectopic muscular differentiation at the venous pole of the heart in RBPJk mutants, revealed by the expression of cardiomyogenic markers such as Tpm1, ␣-SMA, cardiac troponin T, and cardiac actin suggests that muscularization of the SV horns had occurred prematurely.…”

Section: Notch Signaling Inactivation Alters CI Differentiation By Inmentioning

confidence: 99%

Differential Notch Signaling in the Epicardium Is Required for Cardiac Inflow Development and Coronary Vessel Morphogenesis

Monte

Casanova

Guadix

et al. 2011

Circulation Research

151

134

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Rationale:The proepicardium is a transient structure comprising epicardial progenitor cells located at the posterior limit of the embryonic cardiac inflow. A network of signals regulates proepicardial cell fate and defines myocardial and nonmyocardial domains at the venous pole of the heart. During cardiac development, epicardial-derived cells also contribute to coronary vessel morphogenesis.Objective: To study Notch function during proepicardium development and coronary vessel formation in the mouse. Methods and Results:Using in situ hybridization, RT-PCR, and immunohistochemistry, we find that Notch pathway elements are differentially activated throughout the proepicardial-epicardial-coronary transition. Analysis of RBPJk-targeted embryos indicates that Notch ablation causes ectopic procardiogenic signaling in the proepicardium that in turn promotes myocardial differentiation in adjacent mesodermal progenitors, resulting in a premature muscularization of the sinus venosus horns. Epicardium-specific Notch1 ablation using a Wt1-Cre driver line disrupts coronary artery differentiation, reduces myocardium wall thickness and myocyte proliferation, and reduces Raldh2 expression. Ectopic Notch1 activation disrupts epicardium development and causes thinning of ventricular walls. T he early vertebrate heart consists of 2 tissue layers, the outer myocardium and the inner endocardium. At embryonic day (E)9.5 in mice, a third tissue, the epicardium, migrates to envelop the outer surface of the myocardium, actively participating in coronary vessels (CVs) morphogenesis and compact ventricular myocardium growth. 1 Epicardial progenitors are found in the proepicardium, a grape-like structure with characteristic protrusions (proepicardial villi). The proepicardium arises by E9.0 through local proliferation of the coelomic epithelium covering the septum transversum at the posterior limit (venous pole) of the heart. 2 The mesodermal progenitors underneath the proepicardium are often referred to as "posterior pericardial mesoderm," 3 a term that refers to topology rather than an embryological relation to the pericardial membranes. The venous pole of the heart provides the developing heart with myocardium, 4 a process that in the mouse finishes with the muscularization of the sinus horns. 5 The completion of the primitive epicardial epithelium covering the myocardium is followed by the appearance of the subepicardium, 1 an abundant extracellular matrix separating epicardium and myocardium. Concomitantly, the epicardium undergoes an epithelial-tomesenchymal transition (EMT) and populates the subepicardium with mesenchymal epicardial-derived cells (EPDCs), that contribute to the development of CVs and cardiac interstitium. 1 Proepicardial cells (proEPCs) can differentiate in vivo and in vitro into vascular/fibroblastic cell types or myocardium depending on the conditions. 3 A recent study proposed that proepicardial fate depends on the balance between Bmps and Fgfs signals, Bmps promoting myocardial differentiation and Fgfs f...

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Section: Notch Signaling Inactivation Alters CI Differentiation By Inmentioning

confidence: 99%

Differential Notch Signaling in the Epicardium Is Required for Cardiac Inflow Development and Coronary Vessel Morphogenesis

Monte

Casanova

Guadix

et al. 2011

Circulation Research

151

134

View full text Add to dashboard Cite

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“…This structure extends many tissue processes and covers the surface of the naked myocardium of the looped heart in avian species (Hiruma and Hirakow, 1989;Ho and Shimada, 1978;Viragh and Challice, 1981). Bone Morphogenetic Protein (BMP) has been identified as a factor that may be involved in controlling the timing and direction of proepicardial protrusion towards the heart (Ishii et al, 2010). The transcription factor GATA4 has been found to be strongly expressed in the proepicardium and is required for the formation of the epicardium (Watt et al, 2004).…”

Section: Development Of Coronary Vesselsmentioning

confidence: 99%

Cardiac Vasculature: Development and Pathology

Watanabe¹,

Wikenheiser²,

Ramírez-Bergeron³

et al. 2011

Vasculogenesis and Angiogenesis - From Embryonic Development to Regenerative Medicine

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“…The results of ectopic Bmp2 expression in chicken myocardium suggest a model in which Bmps (presumably Bmp2 and Bmp4) expressed in the atrioventricular (AV) canal direct PE protrusion toward the heart tube. 30 In mammals, the predominant mode of PE cell transfer to the heart seems to be the release of PE cell cysts to the pericardial cavity, with the PE connecting to the heart relatively late in epicardial development. 3,4 Once PE cells adhere to the myocardial surface, they flatten and spread to form a characteristic cobblestone epithelial monolayer ( Figure 3A).…”

Section: Formation Of the Epicardium And Its Spreading Over The Myocamentioning

confidence: 99%

“…29 In addition, Bmp2 expression is crucial for attachment of PE cells to the heart. 30 All these events require highly patterned expression of Bmp2 in the PE/septum transversum region. 31 Bmps thus can be postulated to play a role in establishing the posteriormost myocardial limit (venous pole) of the developing heart.…”

Section: Signals Involved In Pe Specificationmentioning

confidence: 99%

Signaling During Epicardium and Coronary Vessel Development

Pérez‐Pomares

Pompa

2011

Circulation Research

133

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Abstract:The epicardium, the tissue layer covering the cardiac muscle (myocardium), develops from the proepicardium, a mass of coelomic progenitors located at the venous pole of the embryonic heart. Proepicardium cells attach to and spread over the myocardium to form the primitive epicardial epithelium. The epicardium subsequently undergoes an epithelial-to-mesenchymal transition to give rise to a population of epicardiumderived cells, which in turn invade the heart and progressively differentiate into various cell types, including cells of coronary blood vessels and cardiac interstitial cells. Epicardial cells and epicardium-derived cells signal to the adjacent cardiac muscle in a paracrine fashion, promoting its proliferation and expansion. Recently, high expectations have been raised about the epicardium as a candidate source of cells for the repair of the damaged heart. Because of its developmental importance and therapeutic potential, current research on this topic focuses on the complex signals that control epicardial biology. This review describes the signaling pathways involved in the different stages of epicardial development and discusses the potential of epicardial signals as targets for the development of therapies to repair the diseased heart. (Circ Res. 2011;109:1429-1442.)

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BMP Signals Promote Proepicardial Protrusion Necessary for Recruitment of Coronary Vessel and Epicardial Progenitors to the Heart

Cited by 80 publications

References 78 publications

Differential Notch Signaling in the Epicardium Is Required for Cardiac Inflow Development and Coronary Vessel Morphogenesis

Differential Notch Signaling in the Epicardium Is Required for Cardiac Inflow Development and Coronary Vessel Morphogenesis

Cardiac Vasculature: Development and Pathology

Signaling During Epicardium and Coronary Vessel Development

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