Modulatory effect of resveratrol on 5-azacytidine-induced cardiac differentiation of human adipose-derived mesenchymal stem cells.

BACKGROUND: Heart failure is a major global health challenge, and regeneration of damaged myocardium remains limited. Mesenchymal stem cells, particularly adipose-derived mesenchymal stem cells, have potential for cardiac regeneration; however, efficient strategies for cardiac differentiation remain unclear. Resveratrol has been reported to promote cardiac differentiation and improve cell survival, but its modulatory effect on 5-azacytidine-induced cardiac differentiation in human adipose-derived mesenchymal stem cells remains unclear. This study aimed to evaluate the effect of resveratrol on 5-azacytidine-induced cardiac differentiation. METHODS: Cells were treated with 5-azacytidine alone or in combination with different concentrations of resveratrol (5,10, and 20 μM). Cell viability was measured using the MTT assay after 72 h, and cardiac gene expression was analyzed using real-time PCR after 21 days. Cells were examined by an inverted microscope. RESULTS: 5-azacytidine significantly reduced cell viability, while resveratrol partially alleviated this cytotoxicity. Resveratrol enhanced the expression of cardiac-related genes, including TNNT2, MYOD1, and GATA4. However, co-administration of both agents did not improve the reduced efficacy for some markers. Microscopic examination revealed cellular changes, including perinuclear clear regions that appeared to be consistent with cytoplasmic lipid droplet accumulation in several groups. The Res 20 group showed cell-to-cell junctions morphologically resembling intercalated disc-like structures, suggesting morphological changes associated with a cardiomyocyte-like phenotype. No spontaneous beating was observed in any group during the induction period. CONCLUSION: Resveratrol improved the cardiac induction profile by enhancing the expression of cardiac-related genes. Although it showed a trend toward reducing 5-azacytidine-induced cytotoxicity, this effect was not statistically significant.