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Cellular and Molecular Mechanisms of Heart Development: Implications for Heart Disease and Regeneration

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 31 March 2024 | Viewed by 7072

Special Issue Editor

IGF, CNRS, INSERM, Université de Montpellier, Labex ICST, F-34094 Montpellier, France
Interests: molecular mechanisms; cardiac development; cardiac disease; cardiac regeneration; heart regeneration

Special Issue Information

Dear Colleagues, 

The human heart is one of the first organs to develop and can continuously pump blood around the body for decades of human life, long after it is evolutionarily required. Heart development is an intricate process that commences when clusters of cells form the primitive heart tube, which subseqeuntly undergoes dynamic changes in morphology and cellular composition before finally establishing a fully functional and mature heart. The cellular and molecular process that drive cardiac development are finely balanced, and any disruption can lead to a variety of cardiac diseases. The recent advances in genome editing using CRISPR/Cas9, coupled with the rise of next-generating sequencing and single-cell transcriptomics, is allowing us to rapidly gain insights into the molecular and cellular processes that drive cardiac development, which may also be associated with not only cardiac disease, but also the tantalising prospect of cardiac regeneration. Indeed, with the aid of animal models that are capable of cardiac regeneration, it is apparent that the molecular and cellular processes occurring during cardiac development also play fundamental roles during cardiac regeneration. Perhaps the most well-known example is when mature cardiomyocytes dedifferentiate back to an earlier developmental stage, which allows them proliferate and ultimately regenerate the damaged heart. Therefore, understanding more about the cellular and molecular processes that drive heart development will not only increase our understanding of cardiac disease, but also raise the possibility of identifying factors necessary to trigger cardiac regeneration.

This Special Issue aims to highlightthe  recent advances in understanding the cellular and molecular mechanisms of cardiac development and their implications in heart disease and regeneration. The topics may include (but are not limited to):

  • Myocardium/endocardium/epicardium;
  • Neural crest cells;
  • Second heart field;
  • Cardiac fibroblasts;
  • Cardiac valves;
  • Cardiomyopathies;
  • Congenital heart defects;
  • Arrhythmias;
  • Inflammation;
  • iPS-derived models;
  • Animal models;
  • Transcriptomics, e.g., single cell/nuclei.

Dr. Chris Jopling
Guest Editor

Manuscript Submission Information

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Published Papers (5 papers)

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Research

18 pages, 5417 KiB  
Article
Distinct Roles for COMPASS Core Subunits Set1, Trx, and Trr in the Epigenetic Regulation of Drosophila Heart Development
by Jun-yi Zhu, Hangnoh Lee, Xiaohu Huang, Joyce van de Leemput and Zhe Han
Int. J. Mol. Sci. 2023, 24(24), 17314; https://doi.org/10.3390/ijms242417314 - 09 Dec 2023
Viewed by 1061
Abstract
Highly evolutionarily conserved multiprotein complexes termed Complex of Proteins Associated with Set1 (COMPASS) are required for histone 3 lysine 4 (H3K4) methylation. Drosophila Set1, Trx, and Trr form the core subunits of these complexes. We show that flies deficient in any of these [...] Read more.
Highly evolutionarily conserved multiprotein complexes termed Complex of Proteins Associated with Set1 (COMPASS) are required for histone 3 lysine 4 (H3K4) methylation. Drosophila Set1, Trx, and Trr form the core subunits of these complexes. We show that flies deficient in any of these three subunits demonstrated high lethality at eclosion (emergence of adult flies from their pupal cases) and significantly shortened lifespans for the adults that did emerge. Silencing Set1, trx, or trr in the heart led to a reduction in H3K4 monomethylation (H3K4me1) and dimethylation (H3K4me2), reflecting their distinct roles in H3K4 methylation. Furthermore, we studied the gene expression patterns regulated by Set1, Trx, and Trr. Each of the COMPASS core subunits controls the methylation of different sets of genes, with many metabolic pathways active early in development and throughout, while muscle and heart differentiation processes were methylated during later stages of development. Taken together, our findings demonstrate the roles of COMPASS series complex core subunits Set1, Trx, and Trr in regulating histone methylation during heart development and, given their implication in congenital heart diseases, inform research on heart disease. Full article
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10 pages, 4884 KiB  
Communication
Nipbl Haploinsufficiency Leads to Delayed Outflow Tract Septation and Aortic Valve Thickening
by Fanny Boulet, Gaelle Odelin, Alenca Harrington and Thomas Moore-Morris
Int. J. Mol. Sci. 2023, 24(21), 15564; https://doi.org/10.3390/ijms242115564 - 25 Oct 2023
Viewed by 726
Abstract
Cornelia de Lange Syndrome (CdLS) patients, who frequently carry a mutation in NIPBL, present an increased incidence of outflow tract (OFT)-related congenital heart defects (CHDs). Nipbl+/- mice recapitulate a number of phenotypic traits of CdLS patients, including a small body size and cardiac [...] Read more.
Cornelia de Lange Syndrome (CdLS) patients, who frequently carry a mutation in NIPBL, present an increased incidence of outflow tract (OFT)-related congenital heart defects (CHDs). Nipbl+/- mice recapitulate a number of phenotypic traits of CdLS patients, including a small body size and cardiac defects, but no study has specifically focused on the valves. Here, we show that adult Nipbl+/- mice present aortic valve thickening, a condition that has been associated with stenosis. During development, we observed that OFT septation and neural crest cell condensation was delayed in Nipbl+/- embryos. However, we did not observe defects in the deployment of the main lineages contributing to the semilunar valves. Indeed, endocardial endothelial-to-mesenchymal transition (EndMT), analysed via outflow tract explants, and neural crest migration, analysed via genetic lineage tracing, did not significantly differ in Nipbl+/- mice and their wild-type littermates. Our study provides the first direct evidence for valve formation defects in Nipbl+/- mice and points to specific developmental defects as an origin for valve disease in patients. Full article
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19 pages, 4514 KiB  
Article
Cripto Is Targeted by miR-1a-3p in a Mouse Model of Heart Development
by Tiziana Angrisano, Francesca Varrone, Elvira Ragozzino, Annalisa Fico, Gabriella Minchiotti and Mariarita Brancaccio
Int. J. Mol. Sci. 2023, 24(15), 12251; https://doi.org/10.3390/ijms241512251 - 31 Jul 2023
Viewed by 1002
Abstract
During cardiac differentiation, numerous factors contribute to the development of the heart. Understanding the molecular mechanisms underlying cardiac development will help combat cardiovascular disorders, among the leading causes of morbidity and mortality worldwide. Among the main mechanisms, we indeed find Cripto. Cripto is [...] Read more.
During cardiac differentiation, numerous factors contribute to the development of the heart. Understanding the molecular mechanisms underlying cardiac development will help combat cardiovascular disorders, among the leading causes of morbidity and mortality worldwide. Among the main mechanisms, we indeed find Cripto. Cripto is found in both the syncytiotrophoblast of ampullary pregnancies and the inner cell mass along the primitive streak as the second epithelial–mesenchymal transformation event occurs to form the mesoderm and the developing myocardium. At the same time, it is now known that cardiac signaling pathways are intimately intertwined with the expression of myomiRNAs, including miR-1. This miR-1 is one of the muscle-specific miRs; aberrant expression of miR-1 plays an essential role in cardiac diseases. Given this scenario, our study aimed to evaluate the inverse correlation between Cripto and miR-1 during heart development. We used in vitro models of the heart, represented by embryoid bodies (EBs) and embryonic carcinoma cell lines derived from an embryo-derived teratocarcinoma in mice (P19 cells), respectively. First, through a luciferase assay, we demonstrated that Cripto is a target of miR-1. Following this result, we observed that as the days of differentiation increased, the Cripto gene expression decreased, while the level of miR-1 increased; furthermore, after silencing miR-1 in P19 cells, there was an increase in Cripto expression. Moreover, inducing damage with a cobra cardiotoxin (CTX) in post-differentiation cells, we noted a decreased miR-1 expression and increased Cripto. Finally, in mouse cardiac biopsies, we observed by monitoring gene expression the distribution of Cripto and miR-1 in the right and left ventricles. These results allowed us to detect an inverse correlation between miR-1 and Cripto that could represent a new pharmacological target for identifying new therapies. Full article
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13 pages, 2572 KiB  
Article
Prolonged Piezo1 Activation Induces Cardiac Arrhythmia
by Laura Rolland, Angelo Giovanni Torrente, Emmanuel Bourinet, Dounia Maskini, Aurélien Drouard, Philippe Chevalier, Chris Jopling and Adèle Faucherre
Int. J. Mol. Sci. 2023, 24(7), 6720; https://doi.org/10.3390/ijms24076720 - 04 Apr 2023
Cited by 3 | Viewed by 1583
Abstract
The rhythmical nature of the cardiovascular system constantly generates dynamic mechanical forces. At the centre of this system is the heart, which must detect these changes and adjust its performance accordingly. Mechanoelectric feedback provides a rapid mechanism for detecting even subtle changes in [...] Read more.
The rhythmical nature of the cardiovascular system constantly generates dynamic mechanical forces. At the centre of this system is the heart, which must detect these changes and adjust its performance accordingly. Mechanoelectric feedback provides a rapid mechanism for detecting even subtle changes in the mechanical environment and transducing these signals into electrical responses, which can adjust a variety of cardiac parameters such as heart rate and contractility. However, pathological conditions can disrupt this intricate mechanosensory system and manifest as potentially life-threatening cardiac arrhythmias. Mechanosensitive ion channels are thought to be the main proponents of mechanoelectric feedback as they provide a rapid response to mechanical stimulation and can directly affect cardiac electrical activity. Here, we demonstrate that the mechanosensitive ion channel PIEZO1 is expressed in zebrafish cardiomyocytes. Furthermore, chemically prolonging PIEZO1 activation in zebrafish results in cardiac arrhythmias. indicating that this ion channel plays an important role in mechanoelectric feedback. This also raises the possibility that PIEZO1 gain of function mutations could be linked to heritable cardiac arrhythmias in humans. Full article
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19 pages, 3567 KiB  
Article
Intravenous Nicotinamide Riboside Administration Has a Cardioprotective Effect in Chronic Doxorubicin-Induced Cardiomyopathy
by Ekaterina Podyacheva, Natalia N.Yu., Vsevolod V.A., Daria Mukhametdinova, Irina Goncharova, Irina Zelinskaya, Eric Sviridov, Michael Martynov, Svetlana Osipova and Yana Toropova
Int. J. Mol. Sci. 2022, 23(21), 13096; https://doi.org/10.3390/ijms232113096 - 28 Oct 2022
Cited by 4 | Viewed by 1962
Abstract
Doxorubicin, which is widely used to treat a broad spectrum of malignancies, has pronounced dose-dependent side effects leading to chronic heart failure development. Nicotinamide riboside (NR) is one of the promising candidates for leveling the cardiotoxic effect. In the present work, we performed [...] Read more.
Doxorubicin, which is widely used to treat a broad spectrum of malignancies, has pronounced dose-dependent side effects leading to chronic heart failure development. Nicotinamide riboside (NR) is one of the promising candidates for leveling the cardiotoxic effect. In the present work, we performed a comparative study of the cardioprotective and therapeutic actions of various intravenous NR administration modes in chronic doxorubicin-induced cardiomyopathy in Wistar rats. The study used 60 mature male SPF Wistar rats. The animals were randomized into four groups (a control group and three experimental groups) which determined the doxorubicin (intraperitoneally) and NR (intravenous) doses as well as the specific modes of NR administration (combined, preventive). We demonstrated the protective effect of NR on the cardiovascular system both with combined and preventive intravenous drug administration, which was reflected in a fibrous tissue formation decrease, reduced fractional-shortening decrease, and better antioxidant system performance. At the same time, it is important to note that the preventive administration of NR had a more significant protective effect on the animal organism as a whole. This was confirmed by better physical activity parameters and vascular bed conditions. Thus, the data obtained during the study can be used for further investigation into chronic doxorubicin-induced cardiomyopathy prevention and treatment approaches. Full article
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