Embryonic Stem Cell Differentiation into Cardiac Lineages

The heart is the first organ to form and function during vertebrate development. Heart development is an elaborate process requiring cell specification, cell differentiation, cell migration, morphogenesis and interactions among cells from several embryonic origins. Entry of cells into the cardiac lineage in response to the appropriate signals is coupled to the expression of a set of transcription factors that initiates the program for cardiac gene expression and drives the morphogenic events involved in formation of the multi-chambered heart. The left ventricle is derived from the classical primary heart field, while the right ventricle and outflow tract are derived from a distinct second heart field. Some of the earliest expressed transcription factors that initiate cardiac fate are the homeobox transcription factor NKX2.5, MESP and Brachyury (T).Throughout the myocardium, pools of cardiac progenitor cells (CPCs) participate in the continual replacement of apoptotic cardiomyocytes at a low basal level. Transcriptional regulation of early embryonic cells by factors such as NANOG, OCT4 and SOX2 are what help CPCs to maintain pluripotency. Decreased activity of pluripotency factors is accompanied by increased activity of lineage-specific transcriptional activators such as Brachyury (T) and MESP in the mesoderm lineage. Other transcription factors involved in lineage decisions include GATA4 and HOXB5. The primary and secondary heart fields in turn express unique lineage specific markers. ISL1 is involved in the differentiation of secondary heart field cells, whereas NKX2.5 is a marker of both heart fields. Remnant secondary heart field cells are not only able to differentiate into many cell types, but also persist in the postnatal heart. Conduction cells, muscle cells and endothelial cells are some of the most important cell types to emerge during heart development. Endothelial cells are important for vessel formation, cardiac muscle cells for contractility, and cardiac conduction cells for coordinated electrical activity of the heart.