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.
"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 "
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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).
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