Trophoblast stem-cell-derived exosomes alleviate cardiotoxicity of Doxorubicin via improving Mfn2-mediated mitochondrial fusion

Abstract:Doxorubicin (Dox) is an anticancer drug widely used with the side-effect of cardiotoxicity. The cardiotoxicity of Dox is closely related to mitochondrial damage. Mitochondrial dynamics is a quality control mechanism that usually helps to maintain a healthy mitochondrial pool. Trophoblast stem cell-derived exosomes (TSC-Exos) have been shown to protect cardiomyocytes from DOX-induced cardiotoxicity. To explore whether the cardioprotective role is mediated by the regulation of mitochondrial dynamic mechanism, we isolated TSC-Exos from human trophoblast stem cells by ultracentrifugation and characterized them by Western blot and transmission electron microscopy. We performed cellular experiments with H9c2 cells co-cultured with Dox and TSC-Exos in vitro, and in vivo we established a heart failure model by intraperitoneal injection of Dox. Mice in the treatment group were received additional intracardiac injection of TSC-Exos. Then, the cardiac function, cardiomyocyte apoptosis and mitochondrial fragmentation of the treatment group were ameliorated.Dox caused an increased tendency of mitochondrial fission, which was manifested by a decrease in the average size of mitochondria. By receiving TSC-Exos treatment, this effect was eliminated, and its downstream molecular mechanism was investigated. In summary, these results suggested that TSC-Exos lesson DOX-induced cardiotoxicity through antiapoptotic effect and improving mitochondrial fusion with an increase in Mfn2 expression. Together, this study provides a potential new treatment scheme of TSC-Exos for the treatment of heart failure.