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WIREs Syst Biol Med
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Human cardiomyogenesis and the need for systems biology analysis

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Abstract Cardiovascular disease remains the leading cause of death in the Western world and myocardial infarction is one of the primary facets of this disease. The limited natural self‐renewal of cardiac muscle following injury and restricted supply of heart transplants has encouraged researchers to investigate other means to stimulate regeneration of damaged myocardium. The plasticity of stem cells toward multiple lineages offers the potential to repair the heart following injury. Embryonic stem cells have been extensively studied for their ability to differentiate into early cardiomyocytes, however, the pathway has only been partially defined and inadequate efficiency limits their clinical applicability. Some studies have shown cardiomyogenesis from adult mesenchymal stem cells, from both bone marrow and adipose tissue, but their differentiation pathway remains poorly detailed and these results remain controversial. Despite promising results using stem cells in animal models of cardiac injury, the driving mechanisms behind their differentiation down a cardiomyogenic pathway have yet to be determined. Currently, there is a paucity of information regarding cardiomyogenesis on the systemic level. Stem cell differentiation results from multiple signaling parameters operating in a tightly regulated spatiotemporal pattern. Investigating this phenomenon from a systems biology perspective could unveil the abstruse mechanisms controlling cardiomyogenesis that would otherwise require extensive in vitro testing. WIREs Syst Biol Med 2011 3 666–680 DOI: 10.1002/wsbm.141 This article is categorized under: Developmental Biology > Stem Cell Biology and Regeneration

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Characteristic expression analysis of various stages of cardiomyogenesis, from undifferentiated embryonic stem cell (ESC) to mature cardiomyocyte (CM).

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The canonical Wnt pathway inhibits the natural phosphorylation of β‐catenin, which protects it from proteolytic degradation and allows it to suppress the production of various cardiomyocyte markers. The normal GSK‐3β gene is silenced due to methylation of a CpG island in its promoter. 5‐Azacytidine, however, activates the gene by demethylating the promoter. This activation upregulates GSK‐3β activity in the cell, overriding the canonical Wnt pathway and phosphorylating β‐catenin, which targets it for ubiquitylation and proteolytic destruction. LRP5/6 = LDL receptor protein 5/6, P = phosphate, U = ubiquitin, 5‐aza = 5‐azacytidine, GSK‐3β = glycogen synthase kinase‐3β, C = cytosine nucleoside, G = guanidine nucleoside.

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The transforming growth factor β (TGF‐β) family of growth factors plays an important role in early development. Nodal is essential for germ layer formation, and affects anterior or posterior differentiation in a dose‐depedent fashion. Activin A can act as a surrogate for Nodal, and both factors bind to the receptors ALK4 or ALK7, and ActRIIA or ActRIIB, which will phosphorylate SMAD2 and SMAD3. After association of SMAD2/3 with SMAD4, it will enter the nucleus and act as a transcription factor, and has shown to increase cardiac differentiation, though the pathway is not well defined. BMPs are another TGF‐β growth factor, and will bind to receptors that phosphorylate SMAD 1, 5, and 8. In turn, SMAD 1, 5, and 8 will associate with SMAD4, and act as transcription factors for cardiac‐specific genes such as ATF2, GATA4, and Nkx2.5, which in turn modulate cardiac differentiation. BMP signaling can be inhibited by using Noggin. The developmental pathways of Activin/Nodal and BMP signagling are important regulators of cardiomyogenesis during human embryonic stem cell differentiation.

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