Abstract
Embryonic stem cells (ESCs) are an emerging source for cell-based therapies aimed at repairing damaged organ tissues; however, the efficiency of directed differentiation is low and refinement of differentiation protocols is hampered by incomplete understanding of the mechanisms involved in this process. To find new compounds which can improve the efficiency of directed differentiation of ESCs to cardiomyocytes, we screened several thousand chemical compounds and identified a promising group. All of the compounds found have a common structure of 1H-pyrrole,2,2'-(phenylmethylene)bis. Here we report the potential mechanism of action for 31002 which showed the strongest activity among the compounds selected. In the presence of 31002, 15 times more cardiomyocytes differentiated from ESCs, i.e., 3.5% to 52% of total differentiated cells. Moreover, the cardiomyocytes showed functional characteristics including rhythmic beating and marker gene expression. 31002 inhibited the down-regulation of genes related to the three germ layers in the late stage of ESCs differentiation, implying that 31002 supports a continuous fate commitment of undifferentiated ESCs to the cardiac lineage by prolonging the three germ layer stages. Therefore, compounds in this group, including 31002, might be useful as directed cardiomyogenic differentiation-inducers to produce cells for use in cell therapy aimed at restoring damaged heart tissue.