Estradiol treatment promotes cardiac stem cell (CSC)-derived growth factors, thus improving CSC-mediated cardioprotection after acute ischemia/reperfusion

摘要

Introduction Studies from our group and others have indicated that paracrine function is one of major mechanisms underlying stem cell-mediated cardioprotection. To improve therapeutic efficacy of cardiac stem cells (CSCs), modification of CSCs to enhance their paracrine actions is of great interest. We have shown previously that stem cells from female sex produced greater levels of protective growth factors compared with male stem cells. In addition, 17β-estradiol (E2)-treated mesenchymal stem cells provided better protection in the ischemia/reperfusion (I/R)-injured myocardium compared with untreated cells. In this study, therefore, we hypothesized that (1) treatment with E2 would improve CSC-mediated acute protection of cardiac function after global I/R; and (2) this greater protection in E2-treated CSCs would be attributable to the beneficial effect of E2 on paracrine actions of CSCs. Method CSCs were harvested from C57BL mouse hearts. Myocardial I/R was performed in isolated mouse hearts via a Langendorff model. A total of 0.1 × 10 6/mL of untreated CSCs or E2-treated CSCs was infused into mouse hearts before ischemia or during the initiation of reperfusion. Heart tissue was used for analysis of activation of caspase-3 and STAT3. Secretion of vascular endothelial growth factor and stromal cell-derived factor 1α by CSCs and E2-treated CSCs was determined. In addition, the conditioned medium from the cultivation of CSCs and E2-modified CSCs was used to treat cardiomyocytes during hypoxia. Results E2-treated CSCs produced greater levels of vascular endothelial growth factor and stromal cell-derived factor 1α compared with untreated CSCs. Preischemic infusion of CSCs and E2-treated CSCs improved myocardial function, increased activation of myocardial STAT3 (a prosurvival signaling), and reduced active caspase-3 after acute I/R compared with the vehicle group. The greater protection was observed in E2-treated CSC group than in CSC group. Additionally, infusion of E2-treated CSCs, but not untreated CSCs, during the initiation of reperfusion protected cardiac function after I/R, further indicating the beneficial effect of E2 on CSC protective function. Conclusion Treatment with E2 enhanced CSC-derived protective factor production and improved CSC-mediated protection of cardiac function and myocyte survival after acute I/R, suggesting that in vitro modification of CSCs may improve their therapeutic outcome.