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Embryonic stem (ES) cells can differentiate into specialized cells, including cardiac myocytes, but the efficiency is typically low and the process is incompletely understood. Achieving a high throughput of cardiogenesis from pluripotent cells is therefore a major requirement for future approaches in cardiac cell therapy. Here, we developed a novel ester of hyaluronan linked to both butyric and retinoic acid (HBR), coaxing pluripotent ES cells into a cardiogenic decision. In mouse ES cells, HBR remarkably increased the expression of GATA-4 and Nkx-2.5, acting as cardiac lineage-promoting genes in different animal species, including humans. HBR also enhanced prodynorphin gene expression and the synthesis and secretion of dynorphin B, an endorphin playing a major role in ES cell cardiogenesis. These effects occurred at the transcriptional level. HBR also primed the expression of cardiac-specific transcripts and …