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Glucocorticoid receptor directs cardiogenic mesoderm specification in murine embryonic stem cells by induction of cardiogenic factors in endoderm


Heart failure is the number one cause of death in the developed world. The progression of the disease leads to the loss of cardiomyocytes that cannot be replaced endogenously. Embryonic stem cells (ESCs) can be differentiated in vitro into cardiomyocytes. The identification of drug-like compounds that can enrich the differentiating ESC cultures with cardiomyocyte progenitors would be beneficial to generate and expand cardiomyocyte cultures for research and clinical applications, while also serving as probes to dissect the mechanisms that control differentiation. In order to identify novel signaling proteins and pathways involved in cardiogenesis, we developed a fluorescence-based reporter system to screen chemical libraries for cardiomyocyte- inducing molecules. This was screened against a library of known drugs and small molecule pathway modulators. Active compounds included hydrocortisone and the artificial glucocorticoid Dexamethasone (Dex), which induced 10-fold increase in cardiomyocytes, confirmed by an upregulation of cardiac markers Tbx5, MEF2c, cTnt, alphaMhc, as well as the endothelial cell marker CD31. Ligand activated GR seems to upregulate a cascade of events in Foxa2+ definitive endoderm that begins with Hnf4a induction and results in Sox17 -> Cer1 upregulation. Cer1 is a known Nodal inhibitor and has been shown to promote cardiogenesis by locally blocking Nodal in committed cardiac progenitors (Flk1+, MesP1+) and allowing them to proceed with the cardiac program. Dex does so without affecting meso-endoderm lineage choice. DHP seems to alter the balance between mesoderm and neurectoderm when added early to the cultures, in a time when mesoendoderm specification occurs. Later, once the mesoendoderm has been established, it promotes cardiogenesis by inhibiting Nodal/Activin signaling at the receptor level by a mechanism yet to be elucidated - recent data suggests this might be receptor type specific. It appears to mimic the effects of the natural cardiac inducer Cer-1 by blocking Nodal/Activin/TGFb- and BMP-signaling both in cardiac progenitors, resulting in an augmentation of the a cardiac restricted Flk1+, MesP1+ progenitor population and ultimately of cardiomyocytes. Our results should contribute to a better understanding of the important cross-talk between endoderm and mesoderm progenitors in the establishment and expansion of a cardiac progenitor population

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