Posts in Category: Development

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]

Epithelial Properties of the Second Heart Field

Epithelial Properties of the Second Heart Field

Claudio Cortes, Alexandre Francou, Christopher De Bono, Robert G. Kelly

Epithelial-based models for second heart field (SHF) deployment. A, Regional Wnt5a expression promotes cell intercalation in the posterior SHF conferring a pushing force, whereas increased epithelial cohesiveness in the anterior SHF confers a pulling force. Together, these 2 forces promote SHF cell deployment toward the arterial pole of the heart. B, Segmented apical view of the dorsal pericardial wall epithelium at mouse embryonic day 9.5 (E9.5), with color-coded apical surface area, showing cell elongation in the posterior region (arrows) consistent with regional epithelial stress. C, Active actomyosin complexes visualized using a diphosphorylated nonmuscle myosin (ppMLC2) antibody are isotropically distributed before rupture of the dorsal mesocardium (left). ppMLC2 subsequently accumulates on the long membrane of elongated cells in the SHF (arrows, center); in contrast, active ppMLC2 distribution remains isotropic in Nkx2-5 mutant embryos (right). D, The axis of cell division is oriented toward the arterial pole on both the left and the right sides of the dorsal pericardial wall in wild-type but not in Tbx1 mutant embryos. E, Model linking epithelial tension in the SHF to heart tube elongation through biomechanical feedback. Scale bar: 10 µm. OFT indicates outflow tract. Panel A reproduced from Li et al67 with permission (Copyright ©2016, Elsevier Inc); panels B–D adapted from Francou et al118 with permission (Copyright ©The Author(s), 2017). [Powerpoint File]

Epithelial Properties of the Second Heart Field

Epithelial Properties of the Second Heart Field

Claudio Cortes, Alexandre Francou, Christopher De Bono, Robert G. Kelly

Features of polarized epithelial cells and Wnt signaling pathways. A, Basic features of epithelial cells showing stereotypical apicobasal cell domains and underlying mesenchymal cells. Planar cell polarity, orthogonal to the apicobasal axis, is indicated by the large arrow. B, Detailed schema of the boxed region in A showing tight junctions separating apical and basolateral membrane domains and adherens junctions, focusing on elements discussed in the text. C, Cartoon showing intersections between β-catenin Wnt signaling, noncanonical Wnt signaling, and planar cell polarity pathway components referred to in this review. DVL indicates dishevelled; GSK3, glycogen synthase kinase 3; JNK, Jun N-terminal kinase; LEF, lymphoid enhancer binding factor; LRP, lipoprotein receptor-related protein; and TCF, T-cell factor. [Powerpoint File]

Cardiac Regeneration: Lessons From Development

 

Cardiac Regeneration: Lessons From Development

Francisco X. Galdos, Yuxuan Guo, Sharon L. Paige, Nathan J. VanDusen, Sean M. Wu, William T. Pu

Model of the trabeculation process. During trabeulation, a small fraction of cardiomyocytes (CMs) in the compact myocardium (pink) are first specified as trabeculating CMs (brown). These cells delaminate from the compact myocardium and migrate inward to form the first trabecular CMs. CMs in both compacted and trabecular myocardium further proliferate. This proliferation, together with CM migration and rearrangement, results in protrusion and expansion of the trabecular myocardium (illustration credit: Ben Smith). [Powerpoint File]

Cardiac Regeneration: Lessons From Development

Cardiac Regeneration: Lessons From Development

Francisco X. Galdos, Yuxuan Guo, Sharon L. Paige, Nathan J. VanDusen, Sean M. Wu, William T. Pu

Regulation of cardiac progenitor proliferation and differentiation. A, Schematic showing the anterolateral position of first heart field (FHF) progenitors and dorsomedial position of second heart field (SHF) progenitors at embryonic day (E) 7.5. Canonical wingless-type MMTV integration site family member (WNTs), Sonic Hedgehog (SHH), and fibroblast growth factors (FGFs) are expressed dorsally in the region encompassed by the SHF, whereas noncanonical WNTs, BMP2, and FGF8 are expressed ventrally, where the FHF is present. FHF progenitors make up the cardiac crescent and differentiate before the SHF to form the developing heart tube at E8.0. SHF maintains their proliferative state and elongate the heart tube by migrating and differentiating at the inflow and outflow poles of the heart. B, Noncanonical WNTs, BMP2/4, and FGF8 signaling drives FHF progenitors to differentiates toward the myocyte lineage. Meanwhile, canonical WNT/β-catenin, SHH, and FGFs maintain SHF progenitor proliferation. SHF progenitor migration to the outflow and inflow poles of the heart tube exposes them to BMP2/4 and noncanonical WNTs, which drives SHF progenitors to exit their proliferative state and differentiate. C, Canonical WNT/ β-catenin signaling inhibits the differentiation of cardiac progenitors to the myocytes. BMP signaling activates SMAD4 that binds to the transcription factor HOPX to directly inhibit canonical WNT/β-catenin. Moreover, noncanonical WNTs such as WNT5a and WNT11 also inhibit canonical WNT/β-catenin to drive cardiac progenitor differentiation (illustration credit: Ben Smith). [Powerpoint File]

Cardiac Regeneration: Lessons From Development

Cardiac Regeneration: Lessons From Development

Francisco X. Galdos, Yuxuan Guo, Sharon L. Paige, Nathan J. VanDusen, Sean M. Wu, William T. Pu

Specification of mesodermal precursors. Schematic representing the signaling events leading to mesodermal specification during early development. NODAL (nodal growth differentiation factor) is first expressed proximally at embryonic day (E) 5.0. Through an autoregulatory loop, NODAL activates its own expression throughout the epiblast (shown in light purple) and goes on to induce the expression of NODAL antagonists, LEFTY1 and CER1, in the distal visceral endoderm at E5.5 (DVE). The DVE migrates anteriorly where it specifies the anterior portion of the embryo as shown in the yellow hues at E6.5 to 7.5. The anterior visceral endoderm (AVE, yellow) limits NODAL signaling to the posterior of the embryo. Along with wingless-type MMTV integration site family member 3 (WNT3) and bone morphogenic protein (BMP) signaling, NODAL specifies early primitive streak progenitors to the mesoderm fate. [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]

Lncing Epigenetic Control of Transcription to Cardiovascular Development and Disease

Lncing Epigenetic Control of Transcription to Cardiovascular Development and Disease

Gizem Rizki, Laurie A. Boyer

Future directions for the study of long noncoding RNAs (lncRNAs) in cardiovascular biology. There still remain many unanswered questions about the exact functions and molecular mechanisms of lncRNAs that govern diverse aspects of cardiac physiology. Some of the outstanding questions and promising areas of research are outlined in the schematic. CM indicates cardiomyocyte (illustration credit: Ben Smith). [Powerpoint File]

Lncing Epigenetic Control of Transcription to Cardiovascular Development and Disease

Lncing Epigenetic Control of Transcription to Cardiovascular Development and Disease

Gizem Rizki, Laurie A. Boyer

Epigenetic regulation by cardiovascular long noncoding RNAs (lncRNAs). Mechanisms of action of lncRNAs, such as Bvht, Fendrr, and Mhrt, that regulate cardiac gene expression by modulating chromatin modifying protein complexes (A), and Kcnq-overlapping lncRNA 1 (Kcnq1ot1), which regulates chromatin organization and structure (B) are depicted. BAF indicates Brg1/Brm-associated factor; CM, cardiomyocyte; CP, cardiac progenitor cells; ESCs, embryonic stem cells; MES, mesodermal cells; PRC, polycomb repressive complex; and TrxG/MLL, trithorax/mixed lineage leukemia (illustration credit: Ben Smith). [Powerpoint File]

Lncing Epigenetic Control of Transcription to Cardiovascular Development and Disease

Lncing Epigenetic Control of Transcription to Cardiovascular Development and Disease

Gizem Rizki, Laurie A. Boyer

Long noncoding RNAs in the transcriptional circuitry of cardiovascular development. A, Many long noncoding RNAs (lncRNAs) are important for the development of different cell types in the cardiovascular system. Specific examples important for developmental transitions, such as Braveheart and Fendrr, as well as formation of cardiovascular cell types, such as Sencr and Malat1 are depicted. B, Transcriptional profiling studies have identified many lncRNAs that are differentially expressed during cardiac development. Many of these transcripts still await validation and further characterization (illustration credit: Ben Smith). [Powerpoint File]

Investigating the Transcriptional Control of Cardiovascular Development

Investigating the Transcriptional Control of Cardiovascular Development

Irfan S. Kathiriya*, Elphège P. Nora*, Benoit G. Bruneau

Studying cardiac regulatory elements. A, Left, Evolutionary constraints on some regulatory elements render them identifiable by comparative genomics, as exemplified by enhancers upstream of mouse Nkx2-5.86 Right, Combinations of specific chromatin features can reveal potential regulatory elements active in a given cell type. B, Left, Enhancer activity is classically tested by an ability of candidate elements to drive tissue- or stage-specific activity of a reporter. Middle, New technologies, such as SIF-seq,87 allow screening of large genomic neighborhoods for tissue-specific enhancers. Right, Genome Regulatory Organization Mapping with Integrated Transposons92 is a technology that can reveal integrated regulatory inputs exerted at a locus. [Powerpoint FIle]