Generation of heart and vascular system in rodents by blastocyst complementation.

Generating organs from stem cells through blastocyst complementation is a promising approach to meet the clinical need for transplants. In order to generate rejection-free organs, complementation of both parenchymal and vascular cells must be achieved, as endothelial cells play a key role in graft rejection. Here, we used a lineage-specific cell ablation system to produce mouse embryos unable to form both the cardiac and vascular systems.

A Human Hereditary Cardiomyopathy Shares a Genetic Substrate With Bicuspid Aortic Valve.

Background: The complex genetics underlying human cardiac disease is evidenced by its heterogenous manifestation, multigenic basis, and sporadic occurrence. These features have hampered disease modeling and mechanistic understanding. Here, we show that 2 structural cardiac diseases, left ventricular noncompaction (LVNC) and bicuspid aortic valve, can be caused by a set of inherited heterozygous gene mutations affecting the NOTCH ligand regulator MIB1 (MINDBOMB1) and cosegregating genes.

In Vivo and In Vitro Cartilage Differentiation from Embryonic Epicardial Progenitor Cells.

The presence of cartilage tissue in the embryonic and adult hearts of different vertebrate species is a well-recorded fact. However, while the embryonic neural crest has been historically considered as the main source of cardiac cartilage, recently reported results on the wide connective potential of epicardial lineage cells suggest they could also differentiate into chondrocytes. In this work, we describe the formation of cardiac cartilage clusters from proepicardial cells, both in vivo and in vitro.

Training biochemistry students in experimental developmental biology: Induction of cardia bifida formation in the chick embryo.

A high variety of experimental model organisms have been used in developmental biology practical lectures. The work with developing embryos is crucial to make students aware of the multiple biological phenomena underlying normal animal embryogenesis and morphogenesis and represent a unique experimental platform to analyze the impact of molecular signaling in the regulation of all these processes. In particular, Biochemistry undergraduate students enjoy both practical and theoretical lectures on the molecular mechanisms of embryonic development, as that allows them for the integration of crucial molecular concepts (e.

Fsp1 cardiac embryonic expression delineates atrioventricular endocardial cushion, coronary venous and lymphatic valve development.

Fsp1 (a.k.a S100A4 or Metastatin) is an intracellular and secreted protein widely regarded as a fibroblast marker.

Cellular identities in an unusual presentation of cyclopia in a chick embryo.

Cyclopia is a congenital anomaly characterized by the presence of a single or partially divided eye in a single orbit at the body midline. This condition is usually associated with other severe facial malformations, such as the absence of the nose and, on rare occasions, the presence of a proboscis located above the ocular structures. The developmental origin of cyclopia in vertebrates is the failure of the embryonic prosencephalon to divide properly during the formation of the two bilateral eyes.

Cell-based therapies for the treatment of myocardial infarction: lessons from cardiac regeneration and repair mechanisms in non-human vertebrates.

Ischemic cardiomyopathy is the cardiovascular condition with the highest impact on the Western population. In mammals (humans included), prolonged ischemia in the ventricular walls causes the death of cardiomyocytes (myocardial infarction, MI). The loss of myocardial mass is soon compensated by the formation of a reparative, non-contractile fibrotic scar that ultimately affects heart performance.

Bmi1-Progenitor Cell Ablation Impairs the Angiogenic Response to Myocardial Infarction.

Objective- Cardiac progenitor cells reside in the heart in adulthood, although their physiological relevance remains unknown. Here, we demonstrate that after myocardial infarction, adult Bmi1 (B lymphoma Mo-MLV insertion region 1 homolog [PCGF4]) cardiac cells are a key progenitor-like population in cardiac neovascularization during ventricular remodeling. Approach and Results- These cells, which have a strong in vivo differentiation bias, are a mixture of endothelial- and mesenchymal-related cells with in vitro spontaneous endothelial cell differentiation capacity.

Myocardial Bmp2 gain causes ectopic EMT and promotes cardiomyocyte proliferation and immaturity.

During mammalian heart development, restricted myocardial Bmp2 expression is a key patterning signal for atrioventricular canal specification and the epithelial-mesenchyme transition that gives rise to the valves. Using a mouse transgenic line conditionally expressing Bmp2, we show that widespread Bmp2 expression in the myocardium leads to valve and chamber dysmorphogenesis and embryonic death by E15.5.

Congenital coronary artery anomalies: a bridge from embryology to anatomy and pathophysiology--a position statement of the development, anatomy, and pathology ESC Working Group.

Congenital coronary artery anomalies are of major significance in clinical cardiology and cardiac surgery due to their association with myocardial ischaemia and sudden death. Such anomalies are detectable by imaging modalities and, according to various definitions, their prevalence ranges from 0.21 to 5.

Coronary stem development in wild-type and Tbx1 null mouse hearts.

Background: Coronary artery (CA) stems connect the ventricular coronary tree with the aorta. Defects in proximal CA patterning are a cause of sudden cardiac death. In mice lacking Tbx1, common arterial trunk is associated with an abnormal trajectory of the proximal left CA.

Signaling during epicardium and coronary vessel development.

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 epicardium-derived cells, which in turn invade the heart and progressively differentiate into various cell types, including cells of coronary blood vessels and cardiac interstitial cells.

Early embryonic vascular patterning by matrix-mediated paracrine signalling: a mathematical model study.

During embryonic vasculogenesis, endothelial precursor cells of mesodermal origin known as angioblasts assemble into a characteristic network pattern. Although a considerable amount of markers and signals involved in this process have been identified, the mechanisms underlying the coalescence of angioblasts into this reticular pattern remain unclear. Various recent studies hypothesize that autocrine regulation of the chemoattractant vascular endothelial growth factor (VEGF) is responsible for the formation of vascular networks in vitro.

Wt1 controls retinoic acid signalling in embryonic epicardium through transcriptional activation of Raldh2.

Epicardial-derived signals are key regulators of cardiac embryonic development. An important part of these signals is known to relate to a retinoic acid (RA) receptor-dependent mechanism. RA is a potent morphogen synthesised by Raldh enzymes, Raldh2 being the predominant one in mesodermal tissues.

Differential Notch signaling in the epicardium is required for cardiac inflow development and coronary vessel morphogenesis.

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.

Integration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formation.

Cardiac valve formation is crucial for embryonic and adult heart function. Valve malformations constitute the most common congenital cardiac defect, but little is known about the molecular mechanisms regulating valve formation and homeostasis. Here, we show that endocardial Notch1 and myocardial Bmp2 signal integration establish a valve-forming field between 2 chamber developmental domains.

Epicardial development in lamprey supports an evolutionary origin of the vertebrate epicardium from an ancestral pronephric external glomerulus.

The epicardium is the outer layer of the vertebrate heart. Both the embryonic epicardium and its derived mesenchyme are critical to heart development, contributing to the coronary vasculature and modulating the proliferation of the ventricular myocardium. The embryonic epicardium arises from an extracardiac, originally paired progenitor tissue called the proepicardium, a proliferation of coelomic cells found at the limit between the liver and the sinus venosus.

Notch signaling is essential for ventricular chamber development.

Ventricular chamber morphogenesis, first manifested by trabeculae formation, is crucial for cardiac function and embryonic viability and depends on cellular interactions between the endocardium and myocardium. We show that ventricular Notch1 activity is highest at presumptive trabecular endocardium. RBPJk and Notch1 mutants show impaired trabeculation and marker expression, attenuated EphrinB2, NRG1, and BMP10 expression and signaling, and decreased myocardial proliferation.

BMP and FGF regulate the differentiation of multipotential pericardial mesoderm into the myocardial or epicardial lineage.

Proepicardial cells give rise to epicardium, coronary vasculature and cardiac fibroblasts. The proepicardium is derived from the mesodermal lining of the prospective pericardial cavity that simultaneously contributes myocardium to the venous pole of the elongating primitive heart tube. Using proepicardial explant cultures, we show that proepicardial cells have the potential to differentiate into cardiac muscle cells, reflecting the multipotency of this pericardial mesoderm.

A modified chorioallantoic membrane assay allows for specific detection of endothelial apoptosis induced by antiangiogenic substances.

Current in vivo angiogenesis assays allow for the assessment of vascular growth inhibition induced by a test substance, but they usually do not provide information about the mechanisms underlying such an inhibition. A potential antiangiogenic mechanism is the triggering of endothelial apoptosis in the growing vessels. Apoptogenic substances can be of interest for antiangiogenic therapy specially if they specifically perform their action on the angiogenic endothelium.

Notch promotes epithelial-mesenchymal transition during cardiac development and oncogenic transformation.

Epithelial-to-mesenchymal transition (EMT) is fundamental to both embryogenesis and tumor metastasis. The Notch intercellular signaling pathway regulates cell fate determination throughout metazoan evolution, and overexpression of activating alleles is oncogenic in mammals. Here we demonstrate that Notch activity promotes EMT during both cardiac development and oncogenic transformation via transcriptional induction of the Snail repressor, a potent and evolutionarily conserved mediator of EMT in many tissues and tumor types.

Origin of coronary endothelial cells from epicardial mesothelium in avian embryos.

It has been established that coronary vessels develop through self-assembly of mesenchymal vascular progenitors in the subepicardium. Mesenchymal precursors of vascular smooth muscle cells and fibroblasts are known to originate from an epithelial-to-mesenchymal transformation of the epicardial mesothelium, but the origin of the coronary endothelium is still obscure. We herein report that at least part of the population of the precursors of the coronary endothelium are epicardially-derived cells (EPDCs).

Cellular precursors of the coronary arteries.

Coronary vessels develop from a primary vascular network that differentiates in the subepicardium through a process of vasculogenesis, that is, self-assembly of mesenchymal vascular progenitors. Further growth of the subepicardial vascular plexus through a complex process of angiogenesis, vascular remodeling, and arterialization of specific branches gives rise to the definitive coronary system. This report is intended to summarize current knowledge on the origin of the coronary vascular progenitors and to provide new insights suggested by recent findings.

[The epicardium and epicardial-derived cells: multiple functions in cardiac development].

The epicardium develops from an extracardiac primordium, the proepicardium, which is constituted by a cluster of mesothelial cells located on the cephalic and ventral surface of the liver-sinus venosus limit (avian embryos) or on the pericardial side of the septum transversum (mammalian embryos). The proepicardium contacts the myocardial surface and gives rise to a mesothelium, which grows and progressively lines the myocardium. The epicardium generates, through a process of epithelial-mesenchymal transition, a population of epicardial-derived cells (EPDC).