Myocardial Notch Signaling Reprograms Cardiomyocytes to a Conduction-Like Phenotype
ABSTRACT Notch signaling has previously been shown to play an essential role in regulating cell fate decisions and differentiation during cardiogenesis in many systems including Drosophila, Xenopus, and mammals. We hypothesized that Notch may also be involved in directing the progressive lineage restriction of cardiomyocytes into specialized conduction cells.
In hearts where Notch signaling is activated within the myocardium from early development onward, Notch promotes a conduction-like phenotype based on ectopic expression of conduction system-specific genes and cell autonomous changes in electrophysiology. With the use of an in vitro assay to activate Notch in newborn cardiomyocytes, we observed global changes in the transcriptome, and in action potential characteristics, consistent with reprogramming to a conduction-like phenotype.
Notch can instruct the differentiation of chamber cardiac progenitors into specialized conduction-like cells. Plasticity remains in late-stage cardiomyocytes, which has potential implications for engineering of specialized cardiovascular tissues.
- SourceAvailable from: Cristiana Caliceti
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- "These data indicate that Notch signalling is required for expansion of cardiac stem cells and immature cardiomyocytes but that needs to be downregulated to achieve terminal differentiation. Transient Notch 1 re-activation in cardiomyocytes induces transcription of genes conferring a contractile phenotype.29 Additionally, Notch 1 re-activation in cardiomyocytes in ischemic heart reduces apoptosis by activating Akt, a pathway linked to cell survival.30 "
ABSTRACT: The recent increase in human lifespan, coupled with unhealthy diets and lifestyles have led to an unprecedented increase in cardiovascular diseases. Even in the presence of a wide range of therapeutic options with variable efficacy, mortality due to heart failure is still high and there is a need to identify new therapeutic targets. Genetic and in vitro studies have implicated the Notch signalling in the development and maintenance of the cardiovascular system through a direct effect on biological functions of vascular cells (endothelial and vascular smooth muscle cells) and cardiomyocytes. Notch signalling is also involved in the modulation of inflammation, which plays a major role in causing and exacerbating cardiovascular diseases. The Notch pathway could represent a new therapeutic target for the treatment of cardiovascular diseases.09/2013; 2013(4):364-371. DOI:10.5339/gscp.2013.44
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ABSTRACT: The explosion of stem cell research in cardiology has yielded an increasing recognition that understanding developmental cell fate decisions is critical for everything from disease models to cellular therapeutics. However, the biology is particularly rich and complex and has not yielded easily to traditional investigative methods. One area of intense focus is the study of the cues responsible for the development of specialized conduction tissues in the heart. Direction of native cells or exogenous cells into the conduction system lineage might offer therapeutic insights into degenerative conduction disease. (SELECT FULL TEXT TO CONTINUE).Circulation 07/2012; 126(9):1009-11. DOI:10.1161/CIRCULATIONAHA.112.126482 · 14.95 Impact Factor
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ABSTRACT: Perturbations in cardiac development result in congenital heart disease, the leading cause of birth defect-related infant morbidity and mortality. Advances in cardiac developmental biology have significantly augmented our understanding of signalling pathways and transcriptional networks underlying heart formation. Cardiogenesis is initiated with the formation of mesodermal multipotent cardiac progenitor cells, and is governed by cross-talk between developmental cues emanating from endodermal, mesodermal and ectodermal cells. The molecular and transcriptional machineries that direct the specification and differentiation of these cardiac precursors are part of an evolutionarily conserved program that includes the Nkx-, Gata-, Hand-, T-box and Mef2-family of transcription factors. Unravelling the hierarchical networks governing the fate and differentiation of cardiac precursors is crucial for our understanding of congenital heart disease and future stem cell-based and gene therapies. Recent molecular and genetic lineage analyses have revealed that subpopulations of cardiac progenitor cells follow distinctive specification and differentiation paths, which determine their final contribution to the heart. In the last decade, progenitor cells that contribute to the arterial pole and right ventricle have received much attention, as abnormal development of these cells frequently results in congenital defects of the aortic and pulmonary outlets, representing the most commonly occurring congenital cardiac defects. In this review, we provide an overview of the building plan of the vertebrate four-chambered heart, with a special focus on cardiac progenitor cell specification, differentiation and deployment during arterial pole development. © 2013 The Authors Acta Physiologica © 2013 Scandinavian Physiological Society.Acta Physiologica 01/2013; 207(4). DOI:10.1111/apha.12061 · 4.25 Impact Factor