Résumé :
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Human embryonic stem cells (HUESCs) are derived as their mouse counterpart from early embryos (i.e. blastocyst stage). Recent studies using stem cells derived from mouse epiblast suggest that HUESC represent a slightly later stage of development than mouse ESC, questioning the molecular mechanisms underlying both their self-renewal and their specification towards various cell fates. Herein, we provide evidence that the main genetic and epigenetic mechanisms that we recently uncovered in mouse ESC and which drive ESCs toward a cardiac lineage are fully conserved in HUESCs. Indeed, the BMP2-dependent canonical cardiogenic pathway is functional in HUESCs. BMP2 switches on a similar pattern of gene expression in both mouse and HUESCs. A change in the methylation state of mesodermal and cardiac gene promoters, already poised to activation, precedes this genetic program. Thus, we report that most of the basic genetic and epigenetic transcriptional events are fully conserved in HUESCs. BMP2 ensures a tune regulation of these events to drive HUESCs toward a cardiogenic fate. These findings can be translated in preclinical studies. We indeed found that BMP2-cardiac committed cells engraft and differentiate in the scar area of post-myocardium infarcted rats, repopulating part of the degenerated area. We confirmed these data in allograft experiments using Rhesus featuring an experimental myocardial infarction in which we transplanted cardiac progenitors derived and sorted out from Rhesus ES cells. The cardiac progenitors further differentiated into the scar area and did not generate any teratomas. Thus, our findings are paving the way of using a population of cardiac progenitors in the clinical arena, including ischemic, genetic and congenital diseases.
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