Pericardial administration of extracellular vesicles derived from bone marrow stem cells improved doxorubicin-induced heart failure with mid range ejection fraction (HFmrEF) in rats

Purpose: This study investigates the therapeutic effects of extracellular vesicles (EVs) derived from bone marrow mesenchymal stem cells (BMSCs) on heart failure in rats through intrapericardial injection. Methods: Initially, doxorubicin was used to induce apoptosis in H9C2 cells, and the protective effects of EVs on these cells were evaluated. EVs were injected into the pericardial cavity of rats with heart failure, followed by real-time in vivo imaging and immunofluorescence detection to confirm the implantation of EVs in the myocardium. Cardiac function was assessed via echocardiography after the pericardial injection. Immunohistochemical techniques were employed to measure the expression of BNP, IL-6, CD31, and VEGFA in rat heart tissue. Additionally, the collagen fiber content in the heart tissue was detected using Masson staining. Results: The results showed that EVs derived from BMSCs at a concentration of 100 μg/ml most effectively promoted the proliferation of H9C2 cells and protected them from doxorubicin-induced damage. Compared to the heart failure group, EV treatment significantly increased LVEF, LVFS, and CO. Following intrapericardial injection of BMSCs, in vivo imaging revealed high-intensity fluorescence signals in the cardiac region, and immunofluorescence confirmed the implantation of EVs in the myocardium. Post-EV treatment, the expression levels of BNP and IL-6 and collagen content in myocardial tissue were significantly reduced, whereas the levels of CD31 and VEGFA were significantly increased. Conclusion: EVs derived from BMSCs, when injected into the pericardial cavity, significantly improved cardiac function in heart failure rats through anti-inflammatory and pro-angiogenic mechanisms.