Umbilical cord mesenchymal stem cells with miR-486-5p overexpression alleviate radiation-induced heart damage by inhibiting ferroptosis

To evaluate the protective effect of miR-486-5p modified umbilical cord mesenchymal stem cells (UCMSC^miR-486) against radiation-induced heart damage (RIHD) and explore the mechanism.

20 Gy of ⁶⁰Coγ-ray was used to establish a model for radiation-induced cardiomyocytes and cardiac damage to mice before UCMSC^miR-486 (1×10⁶ cells per mouse) was treated after radiation. Cell proliferation was detected using CCK-8 kit 48 hours post-treatment. Apoptosis, changes of mitochondrial membrane potential, and the opening of the mitochondrial permeability transition pore of cardiomyocytes were detected by flow cytometry. Small animal ultrasound was used to detect and analyze the cardiac function of mice 42 days later. Changes of cardiac histopathology were detected via HE staining and Masson staining. The ultrastructure of myocardia was observed under a transmission electron microscope (TEM). Real-time quantitative PCR (RT-qPCR) and Western blotting were performed to detect the expressions of ferroptosis-related genes and proteins.

UCMSC^miR-486 markedly reduced radiation-induced apoptosis and especially reactive oxygen species (ROS) levels in AC16 cardiomyocytes and restored both mitochondrial membrane potential and membrane permeability. Intravenous administration of UCMSC^miR-486 via the tail vein significantly increased ejection fraction and shortening fraction in irradiated mouse hearts, decreased the area of myocardial fibrosis, and mitigated mitochondrial ultrastructural damage UCMSC^miR-486 could inhibit ferroptosis of radiated cardiomyocytes and cardiac tissues of mice by modulating the expressions of ferroptosis-related markers, especially acyl-CoA synthetase long chain family member 4 (ACSL4) and glutathione peroxidase 4 (GPX4).

UCMSC^miR-486 can mitigate RIHD by inhibiting ferroptosis. This finding is expected to offer a new strategy for the clinical translation of mesenchymal stem cells.