Regulatory Mechanisms of Cardiac Development and Repair

Ana      Chinchilla; Diego      Franco

Abstract

The heart originates from bilateral primordia that eventually fuse in the embryonic midline leading to a linear tube. Soon after, the heart bends to the right and atrial and ventricular chambers are formed. Progressively each embryonic compartment initiates a process of septation that eventually leads to a four chambered heart with a double circuitry and synchronous contraction. During these developmental events, the growth of the heart and in particular of its myocardial component gradually increases. However, as the heart gets into its mature stage, myocardial growth ceases and concomitantly the myocardium looses its proliferative capacity. In the adult human population, the most frequent cardiac pathologies emanate from a decompensated lost of myocardial function. Therapeutical approaches aiming to add or replace new myocytes to the failing heart are thus highly desired. Embryonic stem cells have a high capacity to give rise to multiple cell types, including myocardial cells, opening new therapeutical possibilities. Unexpectedly discrete adult cell populations have also shown a greater cell plasticity than previously thought, earning therefore much attention as therapeutic targets. These observations have launched initial clinical trials with great hope of clinical benefit. However, it is essential in this respect to initially understand, and eventually control myogenic cell fate determination. Developmental biology of the heart provides a very suitable model for this end. Over the last decade there has been a considerable advance in the understanding of the molecular mechanisms that lead to the determination of the cardiomyocyte lineage and the regulatory mechanisms by which morphogenesis of the heart takes place. Growth factor signalling and transcriptional events controlling cardiac myogenesis have been progressively unravelled. In this review we aim to summarise current data concerning the cardiomyogenic cell fate determination pathways occurring during the natural process of cardiogenesis as compared to the myogenic lineages obtained from embryonic and adult stem cells. Identification of key elements provides important resources to which drugs can be targeted and eventually can result in promising tools to control and expand cardiomyocyte determination.

Keywords: Cardiac development, transcriptional regulation, stem cell-derived cardiomyogenesis, cardiac induction, cell commitment

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