RESUMEN
Mesenchymal stem cells (MSCs) can be differentiated into cardiac, endothelial, and smooth muscle cells. Therefore, MSC-based therapeutic approaches have the potential to deal with the aftermaths of cardiac diseases. However, transplanted stem cells rarely survive in damaged myocardium, proposing that paracrine factors other than trans-differentiation may involve in heart regeneration. Apart from cytokines/growth factors, MSCs secret small, single-membrane organelles named exosomes. The MSC-secreted exosomes are enriched in lipids, proteins, nucleic acids, and microRNA (miRNA). There has been an increasing amount of data that confirmed that MSC-derived exosomes and their active molecule microRNA (miRNAs) regulate signaling pathways involved in heart repair/regeneration. In this review, we systematically present an overview of MSCs, their cardiac differentiation, and the role of MSC-derived exosomes and exosomal miRNAs in heart regeneration. In addition, biological functions regulated by MSC-derived exosomes and exosomal-derived miRNAs in the process of heart regeneration are reviewed.
RESUMEN
BACKGROUND: Cardiovascular diseases remain a major cause of death globally. Cardiac cells once damaged, cannot resume the normal functioning of the heart. Bone marrow derived mesenchymal stem cells (BM-MSCs) have shown the potential to differentiate into cardiac cells. Epigenetic modifications determine cell identity during embryo development via regulation of tissue specific gene expression. The major epigenetic mechanisms that control cell fate and biological functions are DNA methylation and histone modifications. However, epigenetic modifiers alone are not sufficient to generate mature cardiac cells. Various small molecules such as ascorbic acid (AA) and salvianolic acid B (SA) are known for their cardiomyogenic potential. Therefore, this study is aimed to examine the synergistic effects of epigenetic modifiers, valproic acid (VPA) and 5-azacytidine (5-aza) with cardiomyogenic molecules, AA and SA in the cardiac differentiation of MSCs. METHODS AND RESULTS: BM-MSCs were isolated, propagated, characterized, and then treated with an optimized dose of VPA or 5-aza for 24 h. MSCs were maintained in a medium containing AA and SA for 21 days. All groups were assessed for the expression of cardiac genes and proteins through q-PCR and immunocytochemistry, respectively. Results show that epigenetic modifiers VPA or 5-aza in combination with AA and SA significantly upregulate the expression of cardiac genes MEF2C, Nkx2.5, cMHC, Tbx20, and GATA-4. In addition, VPA or 5-aza pretreatment along with AA and SA enhanced the expression of the cardiac proteins connexin-43, GATA-4, cTnI, and Nkx2.5. CONCLUSION: These findings suggest that epigenetic modifiers valproic acid and 5-azacytidine in combination with ascorbic acid and salvianolic acid B promote cardiac differentiation of MSCs. This pretreatment strategy can be exploited for designing future stem cell based therapeutic strategies for cardiovascular diseases.
