ß-Cyclodextrin induces the differentiation of resident cardiac stem cells to cardiomyocytes through autophagy.

ABSTRACT

Cardiac stem cells (CSCs) have emerged as promising cell candidates to regenerate damaged hearts, because of the potential in differentiating to cardiomyocytes. However, the differentiation is difficult to trigger without inducers. Here we reported that ß-cyclodextrin (ß-CD) increased the expression of cardiac transcription factors (Nkx2.5 and GATA4), structural proteins (cardiac Troponin T, cTnt), transcriptional enhancer (Mef2c) and induced GATA4 nucleus translocation in adult resident CSCs, thus ß-CD could be used to enhance myogenic transition. As the differentiation process was accompanied by autophagy, we constructed the Atg5 knockdown cell line by using the Atg5 siRNA lentivirus, and the myogenic conversion was blocked in Atg5 knockdown cells, which suggested that ß-CD induces the cardiomyocytes transition of resident CSCs through autophagy. Furthermore, we found that JNK/STAT3 and GSK3ß/ß-catenin was the downstream pathways of ß-CD-induced autophagy and differentiation using the inhibitors. Moreover, ß-CD performed its functions through improving intracellular cholesterol levels and affecting cholesterol efflux. Collectively, our results reveal that ß-CD as a novel tool to induce myogenic transition of CSCs, which could mobilize the resident CSCs or used together with CSCs to enhance the therapy effects of CSCs on damaged hearts. In addition, the clarified molecular mechanisms supported the new targets for inducing cardiomyocyte differentiation.