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Coordinating Tissue Interactions: Notch Signaling in Cardiac Development and Disease

Program of Cardiovascular Developmental Biology, Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Melchor Fernández Almagro 3, E-28029 Madrid, Spain.
Developmental Cell (Impact Factor: 10.37). 02/2012; 22(2):244-54. DOI: 10.1016/j.devcel.2012.01.014
Source: PubMed

ABSTRACT The Notch pathway is a crucial cell-fate regulator in the developing heart. Attention in the past centered on Notch function in cardiomyocytes. However, recent advances demonstrate that region-specific endocardial Notch activity orchestrates the patterning and morphogenesis of cardiac chambers and valves through regulatory interaction with multiple myocardial and neural crest signals. Notch also regulates cardiomyocyte proliferation and differentiation during ventricular chamber development and is required for coronary vessel specification. Here, we review these data and highlight disease connections, including evidence that Notch-Hey-Bmp2 interplay impacts adult heart valve disease and that Notch contributes to cardiac arrhythmia and pre-excitation syndromes.

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    • "The most prominent NOTCH effectors are basic helix-loop-helix transcription factors, HEY1/2. Endocardial NOTCH/HEY signal integration during endocardial to mesenchymal transition has been shown to be critical in the generation of cardiac valve as a specialized structure [36]. Finally, HAND1 and HAND2 are preferentially expressed in primary and secondary heart fields to develop left and right chamber morphogenesis [37], [38]. "
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    ABSTRACT: The genetic basis of hypoplastic left heart syndrome (HLHS) remains unknown, and the lack of animal models to reconstitute the cardiac maldevelopment has hampered the study of this disease. This study investigated the altered control of transcriptional and epigenetic programs that may affect the development of HLHS by using disease-specific induced pluripotent stem (iPS) cells. Cardiac progenitor cells (CPCs) were isolated from patients with congenital heart diseases to generate patient-specific iPS cells. Comparative gene expression analysis of HLHS- and biventricle (BV) heart-derived iPS cells was performed to dissect the complex genetic circuits that may promote the disease phenotype. Both HLHS- and BV heart-derived CPCs were reprogrammed to generate disease-specific iPS cells, which showed characteristic human embryonic stem cell signatures, expressed pluripotency markers, and could give rise to cardiomyocytes. However, HLHS-iPS cells exhibited lower cardiomyogenic differentiation potential than BV-iPS cells. Quantitative gene expression analysis demonstrated that HLHS-derived iPS cells showed transcriptional repression of NKX2-5, reduced levels of TBX2 and NOTCH/HEY signaling, and inhibited HAND1/2 transcripts compared with control cells. Although both HLHS-derived CPCs and iPS cells showed reduced SRE and TNNT2 transcriptional activation compared with BV-derived cells, co-transfection of NKX2-5, HAND1, and NOTCH1 into HLHS-derived cells resulted in synergistic restoration of these promoters activation. Notably, gain- and loss-of-function studies revealed that NKX2-5 had a predominant impact on NPPA transcriptional activation. Moreover, differentiated HLHS-derived iPS cells showed reduced H3K4 dimethylation as well as histone H3 acetylation but increased H3K27 trimethylation to inhibit transcriptional activation on the NKX2-5 promoter. These findings suggest that patient-specific iPS cells may provide molecular insights into complex transcriptional and epigenetic mechanisms, at least in part, through combinatorial expression of NKX2-5, HAND1, and NOTCH1 that coordinately contribute to cardiac malformations in HLHS.
    PLoS ONE 07/2014; 9(7):e102796. DOI:10.1371/journal.pone.0102796 · 3.23 Impact Factor
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    • "Notch proteins in the endocardium are responsible for modulating myocardial signals (e.g., BMPs) to regulate trabecular formation, chamber specification, and cell proliferation and differentiation (reviewed in [36] [37]). Neural crest cells and the proepicardial organ also contribute to the forming heart. "
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    ABSTRACT: Mammalian heart formation is a complex morphogenetic event that depends on the correct temporal and spatial contribution of distinct cell sources. During cardiac formation, cellular specification, differentiation, and rearrangement are tightly regulated by an intricate signaling network. Over the last years, many aspects of this network have been uncovered not only due to advances in cardiac development comprehension but also due to the use of embryonic stem cells (ESCs) in vitro model system. Additionally, several of these pathways have been shown to be functional or reactivated in the setting of cardiac disease. Knowledge withdrawn from studying heart development, ESCs differentiation, and cardiac pathophysiology may be helpful to envisage new strategies for improved cardiac repair/regeneration. In this review, we provide a comparative synopsis of the major signaling pathways required for cardiac lineage commitment in the embryo and murine ESCs. The involvement and possible reactivation of these pathways following heart injury and their role in tissue recovery will also be discussed.
    BioMed Research International 04/2014; 2014:679168. DOI:10.1155/2014/679168 · 2.71 Impact Factor
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    • "Mutations that affect Notch signaling are associated with several types of congenital heart disease (5). Notch signaling can promote myocardial regeneration, protect the myocardium from ischemia, induce angiogenesis, and inhibit cardiac fibroblast to myofibroblast transformation (CMT). "
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    ABSTRACT: Notch signaling is an evolutionarily ancient, highly conserved pathway important for deciding cell fate, cellular development, differentiation, proliferation, apoptosis, adhesion, and epithelial-to-mesenchymal transition. Notch signaling is also critical in mammalian cardiogenesis, as mutations in this signaling pathway are linked to human congenital heart disease. Furthermore, Notch signaling can repair myocardial injury by promoting myocardial regeneration, protecting ischemic myocardium, inducing angiogenesis, and negatively regulating cardiac fibroblast-myofibroblast transformation. This review provides an update on the known roles of Notch signaling in the mammalian heart. The goal is to assist in developing strategies to influence Notch signaling and optimize myocardial injury repair.
    Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica ... [et al.] 12/2013; DOI:10.1590/1414-431X20133177 · 1.08 Impact Factor
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