Butyric and retinoic mixed ester of hyaluronan A novel differentiating glycoconjugate affording a high throughput of cardiogenesis in embryonic stem cells

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 highly enhanced the yield of spontaneously beating ES-derived cardiomyocytes. These results demonstrate the potential for chemically modifying the gene program of cardiac differentiation in ES cells without the aid of gene transfer technologies and may pave the way for novel approaches in tissue engineering and myocardial regeneration.