Posts Tagged: heart valves

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration

Hui Zhang, Kathy O. Lui, Bin Zhou

Mural cells derived from endocardium in developing heart. A and B, Endocardial cells undergo endothelial to mesenchymal transition to form PDGFRβ+PDGFRα+NG2– mesenchymal cells in the cardiac cushion (black arrows). C and D, Mesenchymal cells migrate into myocardium (white arrows) to form PDGFRβ+PDGFRα–NG2+αSMA+ smooth muscle cells or PDGFRβ+PDGFRα–NG2+αSMA– pericytes. [Powerpoint File]

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration

Hui Zhang, Kathy O. Lui, Bin Zhou

Molecular regulation of endocardial cushion endothelial to mesenchymal transition (EndoMT). Multiple signaling pathways including BMP (bone morphogenetic protein), TGFβ (transforming growth factor-β), and Notch control endocardial contribution to cushion morphogenesis through regulating EndoMT. AVC indicates atrioventricular canal; Msx, msh homeobox; OFT, outflow tract; Rbpj, recombination signal binding protein for immunoglobulin kappa J region; Slug, snail family zinc finger 2; Snail, snail family zinc finger 1; and Twist, twist basic helix–loop–helix transcription factor. [Powerpoint File]

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration

Endocardial Cell Plasticity in Cardiac Development, Diseases and Regeneration

Hui Zhang, Kathy O. Lui, Bin Zhou

Schematic showing the endocardial cell plasticity. Endocardial cell (in the center) differentiates into hematopoietic cell, cushion mesenchyme, coronary, liver vascular endothelial cell, and cardiomyocyte (arrows). Question (?) indicates that the cardiomyocyte fate needs validated. Endocardial cell also contributes to fibroblast, adipocyte, pericyte, and smooth muscle cell (dotted arrows), which might be through intermediate stage of mesenchymal cell. [Powerpoint File]

Endocardial Notch Signaling in Cardiac Development and Disease

Endocardial Notch Signaling in Cardiac Development and Disease

Guillermo Luxán*, Gaetano D’Amato*, Donal MacGrogan*, José Luis de la Pompa

The Notch signaling pathway. In the signaling cell, membrane-bound Notch ligands (Dll1, 3, 4, and Jag1, 2) are characterized by a Delta/Serrate/Lag2 motif (light yellow) located in the extracellular domain. Ligand activity is regulated by the ubiquitin ligase Mind bomb-1 (Mib1) through ubiquitinylation of the intracellular domain (dark yellow squares). In the signal-receiving cell, the Notch receptor (Notch 1–4) is processed at the S1 site by a furin protease, sugar-modified by Fringe in the Golgi and is thought to be inserted into the membrane as a heterodimer with a large extracellular domain (NECD). Ligand–receptor interaction leads to 2 consecutive cleavage events (at S2 and S3 sites, respectively) performed by an ADAM (A Disintegrin And Metalloprotease-containing) protease and presenilin, which release the Notch intracellular domain (NICD) that translocates to the nucleus and binds to CSL (CBF1, Suppressor of Hairless, Lag-1). In the absence of NICD, CSL associates with corepressor proteins (Co-R) and histone deacetylases to repress transcription. After NICD binds to CSL, conformational changes occurring in CSL displace transcriptional repressors. The transcriptional coactivator Mastermind (MAML) is then able to bind to NICD/CSL to form a ternary complex that recruits additional coactivators (Co-A) to activate transcription of a set of target genes. [Powerpoint File]

Endocardial Notch Signaling in Cardiac Development and Disease

Endocardial Notch Signaling in Cardiac Development and Disease

Guillermo Luxán*, Gaetano D’Amato*, Donal MacGrogan*, José Luis de la Pompa

Key events in cardiac development. A, At human embryonic day 14 (hE14) or mouse E7.0. In the gastrulating embryo cardiac progenitors (purple) migrate into the anterior half of the primitive streak to reach the head folds. At E7.5, progenitor cell populations of the first and second heart fields (FHF, purple; SHF, yellow) have fused in the midline of the embryo. At E8.0, the heart tube stage, the approximate contributions of FHF and SHF are shown. B, The heart tube has an outer myocardial layer (light brown) and an inner endocardial endothelium (red) separated by cardiac jelly (gray). C and D, At E9.0, the heart is elongated and looping rightward (C). At E9.5, formation of the atrioventricular canal (AVC) separates the 2 chambers’ territories, the developing atria and ventricles (C). Formation of the valve primordia occurs around E10, together with ventricular chamber development that begins with trabeculae formation in the developing left and right ventricles, and epicardial formation from the proepicardium, located in the venous pole of the heart (D). E, Outflow tract (OFT) and aortic arch arteries (AAA) remodeling is dependent on the cardiac neural crest (CNC) cells. The OFT region of the heart initially exists as a single outflow vessel, which circulates blood into three major pairs of AAAs to join 2 paired dorsal aortae that distribute the blood throughout the embryo. Left, Neural crest cells migrate from the dorsal neural tube, surrounding the aortic arch arteries to the cardiac outflow Middle, The neural crest cells that invest the endothelial tubes of the AAAs differentiate into vascular smooth muscle cells. Right, the AAAs remodel to form the mature aortic arch, with neural crest–derived vascular smooth muscle cells contributing to most of the aortic arch and its major branches. F, Contribution of neural crest (purple) and epicardial (blue)–derived cells (NCDC and EPDC) to the cardiac valves. NCDCs migrate through the pharyngeal arches and into the OFT to initiate the reorganization of the OFT and formation of semilunar valves. EPDCs contribute to the formation of the coronary arteries, the interstitial cells in the myocardium, and the AV valves. In a top view of the septated heart, the relative contributions of NCDCs and EPDCs to cardiac valve leaflets and cusps are shown. G, E13.5-birth. The 4 chambers and valves are shown. The epicardium is shown in gray, and the coronary vessels in red and blue. H, Cushion fusion between E11.5 and E12.5 is a critical step in valve morphogenesis. Aberrant fusion events can lead to bicuspid aortic valve (BAV). R–NC and R–LC fusions might have different causes. I, Scheme depicting the thick ventricular walls of the normal adult heart and the thin and trabeculated walls of a noncompacted heart. In all panels, the ventral aspect of the heart is shown (anterior to the top). A indicates atria; la, left atrium, lv, left ventricle; LVNC, left ventricular noncompaction; mv, mitral valve; pv, pulmonary valve; rv, right ventricle; and tv, tricuspid valve. [Powerpoint File]

Endocardial Notch Signaling in Cardiac Development and Disease

Endocardial Notch Signaling in Cardiac Development and Disease

Guillermo Luxán*, Gaetano D’Amato*, Donal MacGrogan*, José Luis de la Pompa

Endocardial Notch signaling is essential for chamber development. A, Transverse section of an hematoxylin and eosin–stained WT E9.5 heart at the level the left ventricle (lv). The arrow points to a forming trabecula. B, The heart of a E9.5 RBPJk mutant embryo shows a collapsed endocardium (arrowhead) and poorly developed trabeculae (arrow). C, Scheme depicting Notch pathway elements expression the early ventricular myocardium: Mib1 is expressed throughout the endocardium (purple), Dll4 in endocardium at the base of the forming trabeculae (green), where Notch1 is activated (red), triggering signals involved in cardiomyocyte proliferation and differentiation. At this stage, the primitive myocardial epithelium begins to express compact myocardium markers. Images derived from Grego-Bessa et al.3 D, Episcopic 3-dimensional reconstruction of E16.5 WT and E, Mib1flox;cTnT-Cre hearts. Note the thick ventricular walls (brackets) and the small trabecular ridges (arrows) in the WT heart (D) and the thin compact myocardium and noncompacted trabecular in the mutant heart (E). *Disorganized interventricular septum. F, Schematic representation of Notch function during ventricular maturation and compaction. Mib1-Jag1 signaling from the myocardium (blue) activates Notch1 throughout the endocardium (red) to sustain trabecular patterning, maturation, and compaction. Proliferative compact myocardium is defined by the expression of Hey2, Tbx20, and n-myc, whereas the nonproliferative trabecular myocardium is defined by the expression of Anf, Bmp10, and Cx40. Images derived from Luxán et al.4 la indicates left atrium, ra, right atrial; and rv, right ventricle. [Powerpoint File]