Embryonic Cell Differentiation into Cardiac Lineages
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Embryonic Cell Differentiation into Cardiac Lineages
Stem Cells are undifferentiated cells with broad developmental potential. They are able to generate various specialized cell types and, in addition, have the capacity to self-renew and thus to produce undifferentiated progeny that retain Stem Cell features. These properties allow Stem Cells to provide developing organs with appropriate numbers of differentiated cells and to control tissue maintenance, regeneration and repair. The Heart is the first functional organ formed during Embryonic development. Heart development is an elaborate process requiring cell specification, cell differentiation, cell migration, morphogenesis, and interactions among cells from several embryonic origins. It arises from paired regions of dorsolateral mesoderm that are specified by inductive interaction with adjacent tissues. In all vertebrates, the myogenic and endocardial lineages of the Heart develop from Anterior lateral plate mesoderm and underlying endoderm. Myocardium precursor cells of Amphibia and Aves are induced by signals which emanate from the organizer or node, an early embryonic patterning center, and then from anterior endoderm. 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 multichambered heart. The earliest expressed transcription factors that initiate Cardiac fate are the homeobox transcription factor NKX2.5 (NK2 transcription factor related, locus 5 (Drosophila)) and members of the GATA (GATA Binding Protein) family of zinc finger transcription factors, GATA4 (GATA Binding Protein-4), GATA5 (GATA Binding Protein-5), and GATA6 (GATA Binding Protein-6). Equally important roles in heart development have been shown for members of the T-box (Tbx5, Tbx20), basic helix-loop-helix (DHAND, EHAND), and MADS (MCMI, agamous, deficiens, serum response factor) domain (MEF2) families. LIM (a cysteine-rich motif identified in the homeobox genes lin-11, Isl-1, and mec-3) homeodomain transcription factor, which is expressed in a distinct population of Cardiac precursor cells, is essential for the formation of the outflow tract and the right ventricle (Ref.1, 2 & 3).

Throughout the myocardium, pools of CPCs (Cardiac Progenitor Cells) participate in the continual replacement of apoptotic Cardiomyocytes at a low basal level. CPCs are small cells that do not express Cardiac markers and that can self-renew and proliferate. Transcriptional regulation of early embryonic cells by factors such as Nanog, Oct4 (Octamer Binding Transcription Factor-4) and SOX2 (SRY (Sex Determining Region-Y) Box-2) maintains Pluripotency. Decreased activity of Pluripotency factors is accompanied by increased activity of lineage-specific transcriptional activators such as T (Brachyury) and MESP (Mesoderm Posterior homolog (mouse)) in the mesoderm lineage. Mesodermal cells that begin to differentiate into Cardiac cells segregate into two distinct populations of Cardiac progenitor cells. Two populations of Cardiac progenitors, referred to as the Primary and Secondary heart fields, express unique markers of progenitor cells. Isl1 (Isl1 Transcription Factor Lim/Homeodomain) is involved in the differentiation of Secondary heart field cells, whereas the homeodomain-containing transcription factor NKX2.5 is a marker of both heart fields. Remnant Secondary heart field cells not only able to differentiate into many cell types, but also persist in the postnatal heart. The pool of potential CPCs are involved in continual maintenance of the heart by differentiating into several types of Cardiac cell, including Cardiac Muscle cells or Myocytes, Conduction cells, Endothelial cells  and Postnatal Cardiac Progenitors, although the precise lineage potential of distinct subtypes remains to be determined. Endothelial cells are important for vessel formation, Cardiac Muscle cells for contractility, and Cardiac Conduction cells for coordinated electrical activity of the heart. Other transcription factors involved in lineage decisions include GATA4, HF-1b and HOXB5 (Homeobox B5). HF-1b plays a critical role in conduction system lineage formation and the loss of HF-1b leads to a confused electrophysiological identity in Purkinje and ventricular cell lineages, resulting in Cardiac sudden death and marked Tachy and Brady Arrhythmias. The transcription factor GATA4 is a critical regulator of Cardiac gene expression and plays an essential role in promoting Cardiac development and differentiation of the myocardium, as well as in regulating survival and hypertrophic growth of the Adult Heart. HOXB5 is necessary to activate the cell-intrinsic events that regulate the differentiation of Angioblasts and mature endothelial cells from their mesoderm-derived precursors (Ref. 4, 5 & 6).

Cardiac Myocytes, once formed, become organized into a linear Heart tube that undergoes rightward looping in response to an axial signaling system that establishes asymmetry across the left-right axis of the embryo. Subsequent balloon-like growth of the looped Heart tube and septation yield the multichambered Heart. Growth and maturation of Cardiac myocytes within the developing ventricular chambers depends on complex signaling events between adjacent cell layers. Signaling by Neuregulins from the endocardium, a thin layer of cells lining the Cardiac chambers, to the ErbB receptor in the Myocardium is required for growth of the ventricular layer. The Epicardial layer of the Heart also serves as a rich source of signals that stimulate Cardiac growth, such as Retinoic acid and as yet unidentified Peptide Growth Factors. Formation of the Cardiac valves, which are essential for unidirectional blood flow, requires signaling by TGF-Beta family members from the Myocardium to localized swellings of the Endocardium, known as Cardiac cushions. Neural crest cells from the pharyngeal arches also populate the developing Heart and are important in the formation of valves and the interventricular septum and in the patterning of the outflow tract and great arteries (Ref.1, 7 & 8).


Cardiac Conduction cells develop and form the Cardiac conduction system of the Heart. Electrical impulses are propagated through the heart by the Cardiac conduction system and by direct cell-cell coupling of Cardiac myocytes. Important component of conduction system include Sinoatrial Node, Atrioventricular Node and Purkinje fibers. Each heartbeat and synchronized round of Cardiac contraction and relaxation is controlled by Sinoatrial node, the pacemaker of the Heart, which is a specialized cluster of cells in the right Atrium. Purkinje cells are derived from a subpopulation of ventricular Cardiomyocytes in response to signaling by Endothelin-1 and Neuregulins. In addition to key signaling and transcriptional events that directs the Cardiac lineage, microRNAs that are muscle-specific (miR-1 and miR-133) and involved in differentiation of CPCs in the embryo are also believed to be useful in initiating the Cardiogenic programme. Insights into Cardiac development promise to have impact on human disease in many ways, most of which have yet to be realized. The identification of Cardiac control genes permits genetic screening for mutations in affected individuals and families. Research on the basic principles of Cardiogenesis is believed to have an important impact on the understanding of many Cardiac malformations and may give inroads into therapeutic strategies (Ref.1, 9 & 10).