Heart Development
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2021 ◽  
Gaetano D'Amato ◽  
Ragini Phansalkar ◽  
Jeffrey A. Naftaly ◽  
Pamela E Coronado Rios ◽  
Dale O. Cowley ◽  

Regenerating coronary blood vessels has the potential to ameliorate ischemic heart disease, yet there is currently no method of stimulating clinically effective cardiac angiogenesisis. Endocardial cells, a particularly plastic cell type during development, line the heart lumen and are natural coronary vessel progenitors. Their intrinsic angiogenic potential is lost in adults, but studying the endocardial-to-coronary developmental pathway could identify methods of re-instating this process in diseased hearts. Here, we use a combination of mouse genetics and scRNAseq of lineage-traced endothelial cells to identify novel regulators of endocardial angiogenesis and precisely assess the role of Cxcl12/Cxcr4 signaling. Time-specific lineage tracing demonstrated that endocardial cells differentiated earlier than previously thought, largely at mid-gestation. A new mouse line reporting the activity of Cxcr4 revealed that, despite widespread Cxcl12 and Cxcr4 expression, only a small subset of these coronary endothelial cells activated the receptor, which were mostly in arteries. In accordance with these two findings, Cxcr4 deletion in the endocardial lineage only affected artery formation and only when deleted before mid-gestation. Integrating scRNAseq data of coronary endothelial cells from the endocardial lineage at both mid- and late-gestation identified a transitioning population that was specific to the earlier timepoint that specifically expressed Bmp2. Recombinant Bmp2 stimulated endocardial angiogenesis in an in vitro explant assay and in neonatal mouse hearts upon myocardial infarction. Our data shed light on how understanding the molecular mechanisms underlying endocardial-to-coronary transitions can identify new potential therapeutic targets that could promote revascularization of the injured heart.

Circulation ◽  
2021 ◽  
Vol 144 (17) ◽  
pp. 1409-1428
Markus Krane ◽  
Martina Dreßen ◽  
Gianluca Santamaria ◽  
Ilaria My ◽  
Christine M. Schneider ◽  

Background: Complex molecular programs in specific cell lineages govern human heart development. Hypoplastic left heart syndrome (HLHS) is the most common and severe manifestation within the spectrum of left ventricular outflow tract obstruction defects occurring in association with ventricular hypoplasia. The pathogenesis of HLHS is unknown, but hemodynamic disturbances are assumed to play a prominent role. Methods: To identify perturbations in gene programs controlling ventricular muscle lineage development in HLHS, we performed whole-exome sequencing of 87 HLHS parent–offspring trios, nuclear transcriptomics of cardiomyocytes from ventricles of 4 patients with HLHS and 15 controls at different stages of heart development, single cell RNA sequencing, and 3D modeling in induced pluripotent stem cells from 3 patients with HLHS and 3 controls. Results: Gene set enrichment and protein network analyses of damaging de novo mutations and dysregulated genes from ventricles of patients with HLHS suggested alterations in specific gene programs and cellular processes critical during fetal ventricular cardiogenesis, including cell cycle and cardiomyocyte maturation. Single-cell and 3D modeling with induced pluripotent stem cells demonstrated intrinsic defects in the cell cycle/unfolded protein response/autophagy hub resulting in disrupted differentiation of early cardiac progenitor lineages leading to defective cardiomyocyte subtype differentiation/maturation in HLHS. Premature cell cycle exit of ventricular cardiomyocytes from patients with HLHS prevented normal tissue responses to developmental signals for growth, leading to multinucleation/polyploidy, accumulation of DNA damage, and exacerbated apoptosis, all potential drivers of left ventricular hypoplasia in absence of hemodynamic cues. Conclusions: Our results highlight that despite genetic heterogeneity in HLHS, many mutations converge on sequential cellular processes primarily driving cardiac myogenesis, suggesting novel therapeutic approaches.

Rui Xu ◽  
Shaojun Du

Lifeact-GFP is a frequently used molecular probe to study F-actin structure and dynamic assembly in living cells. In this study, we generated transgenic zebrafish models expressing Lifeact-GFP specifically in cardiac muscles to investigate the effect of Lifeact-GFP on heart development and its application to study cardiomyopathy. The data showed that transgenic zebrafish with low to moderate levels of Lifeact-GFP expression could be used as a good model to study contractile dynamics of actin filaments in cardiac muscles in vivo. Using this model, we demonstrated that loss of Smyd1b, a lysine methyltransferase, disrupted F-actin filament organization in cardiomyocytes of zebrafish embryos. Our studies, however, also demonstrated that strong Lifeact-GFP expression in cardiomyocytes was detrimental to actin filament organization in cardiomyocytes that led to pericardial edema and early embryonic lethality of zebrafish embryos. Collectively, these data suggest that although Lifeact-GFP is a good probe for visualizing F-actin dynamics, transgenic models need to be carefully evaluated to avoid artifacts induced by Lifeact-GFP overexpression.

2021 ◽  
Qinchao Zhou ◽  
Lei Lei ◽  
Hefei Zhang ◽  
Shih-Ching Chiu ◽  
Lu Gao ◽  

Cardiac looping and trabeculation are key processes during cardiac chamber maturation. However, the underlying mechanisms remain incompletely understood. Here, we report the isolation, cloning, and characterization of the proprotein convertase furina from the cardiovascular mutant loft in zebrafish. loft is an ethylnitrosourea-induced mutant and has evident defects in the cardiac outflow tract, heart looping and trabeculation, the craniofacial region, and pharyngeal arch arteries. Positional cloning revealed that furina mRNA was barely detectable in loft mutants, and loft failed to complement the TALEN-induced furina mutant pku338, confirming that furina is responsible for the loft mutant phenotypes. Mechanistic studies demonstrated that Notch reporter Tg(tp1:mCherry) signals were largely eliminated in mutant hearts, while over-expression of NICD partially rescued the mutant phenotypes, probably due to the lack of Furina-mediated cleavage processing of Notch1b proteins, the only Notch receptor expressed in the heart. Together, our data suggest a potential post-translational modification of Notch1b proteins via the proprotein convertase Furina in the heart and unveil the function of the Furina-Notch1b axis in cardiac looping and trabeculation in zebrafish and possibly in other organisms.

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1057
Daniela Maria Tanase ◽  
Evelina Maria Gosav ◽  
Anca Ouatu ◽  
Minerva Codruta Badescu ◽  
Nicoleta Dima ◽  

Regardless of the newly diagnostic and therapeutic advances, coronary artery disease (CAD) and more explicitly, ST-elevation myocardial infarction (STEMI), remains one of the leading causes of morbidity and mortality worldwide. Thus, early and prompt diagnosis of cardiac dysfunction is pivotal in STEMI patients for a better prognosis and outcome. In recent years, microRNAs (miRNAs) gained attention as potential biomarkers in myocardial infarction (MI) and acute coronary syndromes (ACS), as they have key roles in heart development, various cardiac processes, and act as indicators of cardiac damage. In this review, we describe the current available knowledge about cardiac miRNAs and their functions, and focus mainly on their potential use as novel circulating diagnostic and prognostic biomarkers in STEMI.

Meixue Chen ◽  
Jing Li ◽  
Jinfeng Wang ◽  
Yuan Le ◽  
Chunfeng Liu

Abstract Sepsis-induced cardiomyopathy (SIC) is a major complication of sepsis. SET and MYND domain containing 1 (SMYD1) has central importance in heart development, and its role in SIC has not been identified. Herein, we found that the expression of SMYD1 was downregulated in myocardial tissues of SIC patients (from GEO database: GSE79962) and lipopolysaccharide (LPS)-induced SIC rats, and LPS-induced H9c2 cardiomyocytes. We used LPS-stimulated H9c2 cells that mimic sepsis in vitro to explore the function of SMYD1 in SIC. MTT assay, LDH and CK-MB release assay, flow cytometry, and ELISA assay showed that SMYD1 overexpression enhanced cell viability, alleviated cell injury, impeded apoptosis, and reduced the level of pro-inflammatory factors and NF-κB activation under the condition of LPS stimulation. Moreover, SMYD1 exerted protective effect on H9c2 cells stimulated with LPS through relieving endoplasmic reticulum (ER) stress. In conclusion, overexpression of SMYD1 alleviates cardiac injury through relieving ER stress during sepsis.

2021 ◽  
Vol 42 (Supplement_1) ◽  
S Srivastava ◽  
F Gunanwan ◽  
S Guenther ◽  
F Ferrazzi ◽  
A Gentile ◽  

Abstract Introduction Trabeculation is a crucial process during ventricular chamber development which describes the protrusion of cardiomyocytes into the lumen of the ventricular chamber to form complex muscular structures called trabeculae. Defects in this process results in various human diseases such as left ventricular non compaction cardiomyopathies and other congenital heart defects. Several cellular mechanisms have been identified underlying trabeculation including tension heterogeneity induced cardiomyocyte selection, depolarization and delamination. However, the molecular mechanisms governing trabeculation are still poorly understood. Purpose Previously, we have shown that Gpr126 is required for trabeculation and heart development in mice and zebrafish. Gpr126 is an adhesion G-protein coupled receptor which is autoproteolytically cleaved into an N-terminal fragment (NTF) and a C-terminal fragment (CTF). Here, we show that NTF and CTF control different cellular processes during trabeculation. Methods and results In-vivo confocal images of hearts of CTF-depleted mutants gpr126st49 (expressing NTF) revealed a multilayered ventricular wall lacking any trabecular projections, which is in contrast to our previous results obtained with morpholinos suggesting that the NTF is sufficient for proper heart development in zebrafish. A molecular characterization of gpr126st49 mutants showed that cardiomyocytes in the multilayer fail to depolarize and relocalize N-cadherin from the lateral to the basal side, indicating that the cardiomyocytes in the multi-layered wall fail to attain a trabecular identity. In addition, these mutants showed significantly upregulated myocardial notch expression, which is known to prevent cardiomyocytes from attaining a trabecular identity. These data suggest that CTF is required for proper formation of trabeculae. We analyzed the full length-depleted mutant gpr126stl47 for trabeculation defects and observed that 17% of gpr126stl47 maternal zygotic mutants exhibited complete absence of trabeculation and 27% hypotrabeculation. Analysis of these mutants revealed that instead of being specifically localized at the junctions, N-cadherin was mainly distributed to the apical and basal side in the compact layer cardiomyocytes. This indicates that the NTF is required for maintaining the cell-cell adhesion in the compact wall. Finally, overexpression of gpr126 in the absence of Erbb2 signaling and blood flow / -or contractility failed to cause multilayering suggesting that Gpr126 is part of the well-established Erbb2 signaling cascade controlling trabeculation. Conclusion Collectively, our data support a model with domain-specific functions of Gpr126 in ventricular chamber development, where the NTF of Gpr126 is required for maintaining the compact wall integrity at the onset of trabeculation by maintaining cell-cell junctions, while the CTF helps in providing trabecular identity to cardiomyocytes through modulation of myocardial notch activity. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): DFG

Development ◽  
2021 ◽  
Christopher J. Derrick ◽  
Eric J. G. Pollitt ◽  
Ashley Sanchez Sevilla Uruchurtu ◽  
Farah Hussein ◽  
Andrew J. Grierson ◽  

During early vertebrate heart development the heart transitions from a linear tube to a complex asymmetric structure, a morphogenetic process which occurs simultaneously with growth of the heart. Cardiac growth during early heart morphogenesis is driven by deployment of cells from the Second Heart Field (SHF) into both poles of the heart. Laminin is a core component of the extracellular matrix (ECM), and although mutations in laminin subunits are linked with cardiac abnormalities, no role for laminin has been identified in early vertebrate heart morphogenesis. We identified tissue-specific expression of laminin genes in the developing zebrafish heart, supporting a role for laminins in heart morphogenesis. Analysis of heart development in lamb1a zebrafish mutant embryos reveals mild morphogenetic defects and progressive cardiomegaly, and that Lamb1a functions to limit heart size during cardiac development by restricting SHF addition. lamb1a mutants exhibit hallmarks of altered haemodynamics, and blocking cardiac contractility in lamb1a mutants rescues heart size and atrial SHF addition. Together this suggests that laminin mediates interactions between SHF deployment and cardiac biomechanics during heart development and growth in the developing embryo.

2021 ◽  
Vol 9 (4) ◽  
pp. 40
Nicholas Francoeur ◽  
Rwik Sen

Heart disease is the leading cause of death in the United States and worldwide. Understanding the molecular mechanisms of cardiac development and regeneration will improve diagnostic and therapeutic interventions against heart disease. In this direction, zebrafish is an excellent model because several processes of zebrafish heart development are largely conserved in humans, and zebrafish has several advantages as a model organism. Zebrafish transcriptomic profiles undergo alterations during different stages of cardiac development and regeneration which are revealed by RNA-sequencing. ChIP-sequencing has detected genome-wide occupancy of histone post-translational modifications that epigenetically regulate gene expression and identified a locus with enhancer-like characteristics. ATAC-sequencing has identified active enhancers in cardiac progenitor cells during early developmental stages which overlap with occupancy of histone modifications of active transcription as determined by ChIP-sequencing. CRISPR-mediated editing of the zebrafish genome shows how chromatin modifiers and DNA-binding proteins regulate heart development, in association with crucial signaling pathways. Hence, more studies in this direction are essential to improve human health because they answer fundamental questions on cardiac development and regeneration, their differences, and why zebrafish hearts regenerate upon injury, unlike humans. This review focuses on some of the latest studies using state-of-the-art technology enabled by the elegant yet simple zebrafish.

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