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WIREs Dev Biol
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Organogenesis of the vertebrate heart

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Abstract Organogenesis of the vertebrate heart involves a complex sequence of events initiating with specification and differentiation of myocardial and endocardial cells in anterior lateral mesoderm shortly after gastrulation, followed by formation and rightward looping of the early heart tube. During looping, the heart tube elongates by addition of second heart field progenitor cells from adjacent pharyngeal mesoderm at the arterial and venous poles. Progressive differentiation is controlled by intercellular signaling events between pharyngeal mesoderm, foregut endoderm, and neural crest‐derived mesenchyme. Regulated patterns of myocardial gene expression and proliferation within the embryonic heart drive morphogenesis of atrial and ventricular chambers, while cardiac cushions, precursors of the definitive valves, form in the atrioventricular and outflow regions. In amniotes, separate systemic and pulmonary circulatory systems arise by septation and remodeling events that divide the atria and ventricles into left and right chambers. Cardiac neural crest cells play a key role in dividing the arterial pole of the heart into the ascending aorta and pulmonary trunk. During the remodeling phase the definitive cardiac conduction system, that coordinates the heartbeat, is established. In addition, the epicardium, critical for regulated ventricular growth and development of the coronary vasculature, spreads over the surface of the heart as an epithelium from which cells invade the myocardium to give rise to diverse cell types including fibroblasts and smooth muscle cells. Cardiogenesis thus involves highly coordinated development of multiple cell types and insight into the different lineage contributions and molecular regulation of each of these steps is expanding rapidly. WIREs Dev Biol 2013, 2:17–29. doi: 10.1002/wdev.68 This article is categorized under: Vertebrate Organogenesis > Musculoskeletal and Vascular

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Epicardial development. (a) Right lateral view of a midgestation heart showing attachment of cells derived from the proepicardial organ (PEO) and spreading of epicardial cells (blue) over the external surface of the heart (black arrows). Endothelial progenitor cells originating from the sinus venosus (red) also spread over the surface of the heart (white arrows). (b) Cartoon showing epicardial‐derived (black arrows) cardiac fibroblasts (CF) and smooth muscle cells (SmM) in the ventricular wall associated with coronary endothelial cells (red, orange). See text for discussion of the contribution of epicardially derived cells to coronary endothelium and myocardium. (c) Scheme showing epicardial contributions to myocardial proliferation and coronary vasculature. Proliferative signals are indicated by gray arrows. CM, compact ventricular myocardium; CV, coronary vascular endothelial cells; ENC, endocardium; EPC, epicardium; LV, left ventricle; OFT, outflow tract; RA, right atrium; RV, right ventricle; T, trabeculae.

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Conduction system morphogenesis. (a) Cartoon showing the origin of different components of the conduction system in the midgestation mouse heart including the sinoatrial node (SAN) at the boundary between the right sinus horn (RSH) and right atrium (RA), slow conducting atrioventricular canal myocardium (AVC, blue), and nascent ventricular trabeculae (green). Fast and slow conducting regions are illustrated by full and broken white arrows, respectively. (b) Configuration of the conduction system in the fetal heart after completion of septation, showing the central conduction system composed of the atrioventricular node (blue, AVN) and atrioventricular (or His) bundle (AVB), connected to the right (RBB) and left (LBB) bundle branches (green). The peripheral ventricular conduction system consists of a network of subendocardial Purkinje fibers in the right (RPF) and left (LPF) ventricles (green). Ventricular myocardium is characterized by subendocardial trabeculae (T) and a compact myocardial layer (CM) adjacent to the epicardium (EPC). An example of clonally related myocytes in different layers of a transmural polyclonal cone (PCC) is illustrated, showing a contribution to compact (dark brown), trabecular (light brown) and conductive (green) myocytes. (c) Summary of the combinatorial positive and negative acting transcription factors regulating gene expression in the SAN. (d) Biphasic development of the ventricular conduction system during which a limited proliferation step follows differentiation of conductive myocytes from a common progenitor with working chamber myocytes. ENC, endocardium; LA, left atrium; LSH, left sinus horn; LV, left ventricle; OFT, outflow tract; RV, right ventricle; VV, venous valve.

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Cardiac septation. (a) Ventricular and outflow tract septation are underway at E12.5. The aorticopulmonary septum (APS) originating between the fourth (PAA4) and sixth (PAA6) pharyngeal arch arteries separates the ascending aorta and pulmonary trunk (PT) and converges with fusing outflow tract cushions. Counterclockwise outflow tract rotation (arrow) positions the ascending aorta above the left ventricle. (b) Septation is complete by E14.5 in the mouse; the aorta (Ao) is connected to the left ventricle and the PT to the right ventricle. Three semilunar valve leaflets form the outlet valves at the base of the ascending aorta (AoV) and pulmonary trunk (PV). The PT is connected to the descending aorta by the arterial duct (DA). Subpulmonary myocardium (blue, SPMc) surrounds the base of the PT. The interventricular septum has muscular (muIVS) and membranous (meIVS) components. (c) Atrial and atrioventricular septation showing the primary (PAS) and secondary (SAS) atrial septa and the dorsal mesenchymal protrusion (DMP). The mitral (MV) and tricuspid (TV) valves connect the atria to the left and right ventricles. IVS, interventricular septum; LA, left atrium; LCCA, left common carotid artery; LSCA, left subclavian artery; LV, left ventricle; RA, right atrium; RCCA, right common carotid artery; RSCA, right subclavian artery; RV, right ventricle; VV, venous valve.

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Chamber morphogenesis. (a) Left lateral view showing ballooning of the ventricular and atrial chambers (brown) and the poorly proliferative atrioventricular (AVC) and outflow tract (OFT) myocardium (blue). (b) Chamber and non‐chamber genetic programs are established by bone morphogenetic protein (BMP) signaling and T‐box transcription factor activity. (c) During ballooning morphogenesis cells from the OFT contribute to the right ventricular free wall while cells from the AVC canal contribute to the left ventricular free wall (white arrows). (d) Cushion development in the OFT and AVC regions of the midgestation heart. Distal outflow tract cushions (d‐OFT) are colonized by neural crest‐derived mesenchyme (orange); proximal outflow tract (p‐OFT) and AVC cushion mesenchyme is derived by epithelial to mesenchymal transition of the underlying endocardium (gray). IC, inner curvature; LA, left atrium; LV, left ventricle; OC, outer curvature; RA, right atrium; RV, right ventricle.

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The second heart field (SHF). (a) The lineage relationship between progenitor cell populations giving rise to different regions of the heart. The outflow tract is exclusively derived from the SHF and left ventricle from the linear heart tube. The lineage relationship with craniofacial skeletal muscles derived from pharyngeal mesoderm is indicated. (b, c) Left lateral view (b) and sagittal section (c) showing anterior (green) and posterior (blue) SHF contributions to the heart at E9.5. Core pharyngeal arch mesoderm of arches 1 (PA1CM) and 2 (PA2CM) is visible in (b). (d) Embryonic heart at midgestation (E10.5) showing parts of the heart derived from the anterior SHF (green), linear heart tube (pink), and posterior SHF (blue). The anterior SHF also gives rise to a cuff of smooth muscle at the arterial pole (SmM). At this stage, the arterial pole of the heart is attached to pharyngeal arch arteries (PAA) 3, 4, and 6. (e) Transverse section at the level of the dotted line in (b) showing juxtaposition between anterior SHF cells (green) and neural crest‐derived mesenchyme (CNC, orange) lateral to and underlying the pharynx (Ph). (f) Enlargement of the boxed area in (e) showing intermingled CNC and mesodermal (Mes) mesenchymal cells and the balance between fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signals regulating proliferation and differentiation during outflow tract elongation. (g) Left lateral view of an E14.5 head showing craniofacial skeletal muscles derived from the first pharyngeal arch (muscles of mastication, light green) and second pharyngeal arch (muscles of facial expression, dark green) pharyngeal arches. A‐SHF, anterior second heart field; AVC, atrioventricular canal; D, dorsal; d‐OFT, distal outflow tract; DPC wall, dorsal pericardial wall; End, endoderm; LA, left atrium; LV, left ventricle; OFT, outflow tract; p‐OFT, proximal outflow tract; P‐SHF, posterior second heart field; RA, right atrium; SoM, somatic mesoderm; V, ventral. Color code as for Figure 1.

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Early heart tube (HT) development. (a) Future cardiac cells gastrulate through the anterior region of the primitive streak (PS) and migrate (arrows) to form lateral anterior mesoderm (AM). (b) The cardiac crescent (CC) forms in anterior splanchnic mesoderm underlying the head folds (HF). Late differentiating second heart field (SHF) cells are positioned medially. (c) Transverse section at the level of the dotted line in (b) showing positive signals from underlying endoderm [bone morphogenetic protein (BMP) and fibroblast growth factor (FGF)] and negative signals from the midline (β‐catenin/WNT). (d) Transcription factors cooperatively activating the cardiomyogenic genetic program. (e) The linear HT is characterized by an anterior arterial pole (AP) and posterior venous pole (VP). (f) Transverse section at the level of the dotted line in (e) showing the ventral HT attached to the dorsal mesocardium (DM) and comprised of an outer myocardial layer (MC) and inner endocardial tube (EC) separated by cardiac jelly (CJ). SHF cells are situated in medial splanchnic mesoderm in the dorsal pericardial wall (DPC wall) underlying the pharynx (Ph). (g) As looping initiates the AP of the HT is attached to the first (PAA1) and second (PAA2) pharyngeal arch arteries. (h) Sagittal section after breakdown of the DM showing the transverse pericardial sinus (TPS), and location of SHF cells in the DPC wall. A, anterior; C, coelom; D, dorsal; End, endoderm; L, lateral; M, medial; N, node; NT, neural tube; P, posterior; PM, paraxial mesoderm; SoM, somatic mesoderm; SpM, splanchnic mesoderm; V, ventral. Color code: pink, early differentiating myocytes and derivatives; green, anterior SHF and derivatives; blue, posterior SHF; yellow, endoderm.

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