Part one. BLOOD OR YOUNG PLASMA AND REGENERATION OF THE CARDIAC MUSCLE (Factors Promoting Cardiogenesis in Vertebrates)

Factors Promoting Cardiogenesis in Vertebrates

Heart is the first organ to form and function in the Embryo, and all subsequent events in the life of the organism depend on the Hearts ability to match its output with the organisms demands for Oxygen and nutrients. Abnormalities in Heart formation, the most common form of Human birth defects, affect nearly 1% of newborns, and their frequency in spontaneously aborted pregnancies is estimated to be tenfold higher. Heart development is an elaborate process requiring Cell specification, Cell differentiation, Cell migration, morphogenesis, and interactions among cells from several embryonic origins. The Heart is formed through multiple developmental steps, which include the determination of the Cardiac field in the mesoderm, differentiation of Cardiac precursor cells, and maturation of the Heart. Entry of cells into the Cardiac lineage is dependent upon appropriate external signals 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. Research in Mice, Birds, Amphibians, Flies and Mammals, as well as in various cell culture systems, has led to the identification of multiple transcription factors and extracellular growth factors whose concerted actions specify the Cardiac lineage in mesodermal progenitor cells. The earliest expressed transcription factors that initiate Cardiac fate are the homeobox transcription factor NKX2.5 (NK2 Transcription Factor Related Locus-5) 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 (T-Box-5), Tbx20 (T-Box-20)), basic helix-loop-helix (dHAND/HAND2 (Heart and Neural crest Derivatives expressed-2), eHAND/HAND1 (Heart and Neural crest Derivatives expressed-1)), 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. Extracellular signals that act upstream of these factors have been primarily identified by their ability to induce Cardiac differentiation in non-cardiac mesoderm. These signals belong to the BMP (Bone Morphogenetic Protein), FGF (Fibroblast Growth Factor), and WNT (Wingless-related MMTV integration site) families of Growth Factors and also include secreted WNT antagonists such as Dkk1 (Dickkopf1) and Crescent (Ref.1 & 2). 

FGF2 (Fibroblast Growth Factor-2) and BMPs play a crucial role in early Cardiomyogenesis. FGF2 is required for the expression of Cardiac transcription factors and the differentiation of mesoderm explants induced by BMP2 (Bone Morphogenetic Protein-2). FGF2 induces mesenchymal cell formation from precardiac mesoderm explants. Other members of the FGF family compensate for the lack of FGF2 expression in the embryo, for instance FGF4 (Fibroblast Growth Factor-4) or FGF8 (Fibroblast Growth Factor-8). BMPs play a vital role in Cardiac development. BMP Receptors are essential for myocyte-dependent functions and signals in Cardiac organogenesis. BMPs like BMP2, BMP4 (Bone Morphogenetic Protein-4) and BMP5 (Bone Morphogenetic Protein-5), BMP7 (Bone Morphogenetic Protein-7), BMP10 (Bone Morphogenetic Protein-10), bind to Serine/threonine kinase receptors, Type-I (ALK3 (Activin Receptor-Like Kinase-3) and ALK6 (Activin Receptor-Like Kinase-6)) and Type-II, BMPRII (Bone Morphogenetic Protein Receptor Type-II), respectively, and form a heteromeric signaling complex acting in series. In the presence of ligand, the Type-II receptor phosphorylates the Type-I receptors, which activate signaling by intracellular effectors SMADs (SMAD (Sma and MAD (Mothers Against Decapentaplegic) Related Proteins) and TAK1 (Transforming Growth Factor-Beta-activated Kinase-1). Among the members of SMADs, SMAD1 (SMAD (Sma and MAD (Mothers Against Decapentaplegic) Related Protein-1), SMAD5 (SMAD (Sma and MAD (Mothers Against Decapentaplegic) Related Protein-5) and SMAD8 (SMAD (Sma and MAD (Mothers Against Decapentaplegic) Related Protein-8) transduce signals from BMPs specifically, while SMAD4 (SMAD (Sma and MAD (Mothers Against Decapentaplegic) Related Protein-4) is a general partner of ligand-specific SMADs. Co-overexpression of SMAD1 and SMAD4 induce differentiation of cardiac precursor cells into Cardiomyocytes and overexpression of SMAD6 (Sma and MAD (Mothers Against Decapentaplegic) Related Protein-6), an inhibitory SMAD blocks the signal transduction and inhibits differentiation of the Cardiac precursor cells into Cardiomyocytes. BMP pathway, on the other hand, is negatively regulated by Noggin. Noggin binds specifically to BMP2 and BMP4 with high affinity and also to BMP7 with lower affinity, thereby abolishing the activity of BMPs by blocking the binding of BMPs to cognate cell surface receptors (Ref.3, 4 & 5).