Abstract Body: Doxorubicin-induced cardiotoxicity is an increasing clinical concern, yet effective therapeutic strategies remain limited. While stem cell therapy has shown potential, its clinical application is hindered by immune rejection and inflammation. Recently, exosomes have emerged as key mediators of stem cell-derived paracrine effects; however, the therapeutic potential of exosomes derived from patients with cardiotoxicity remains unclear.
This study aimed to generate patient-specific iPSC-derived cardiomyocytes (iPSC-CMs) from individuals with doxorubicin-induced cardiotoxicity and to evaluate the functional and therapeutic effects of patient-derived exosomes.
Peripheral blood mononuclear cells (PBMCs) were reprogrammed into iPSCs and differentiated into cardiomyocytes via Wnt signaling modulation. Exosomes were isolated using ultracentrifugation and characterized by TEM, nanoparticle tracking analysis, and expression of exosomal markers (Alix, CD81). A cardiotoxicity model was established by treating normal iPSC-CMs with doxorubicin.
Doxorubicin-treated iPSC-CMs showed impaired calcium handling, characterized by reduced frequency and amplitude and prolonged recovery time, despite preserved cell viability. Patient-derived iPSC-CMs recapitulated these functional abnormalities. Exosomes isolated from both normal- and patient-derived cardiomyocytes displayed typical exosomal features. In the cardiotoxicity model, treatment with patient-derived exosomes significantly improved calcium transient parameters, including increased frequency and amplitude and shortened recovery duration. Notably, the proportion of arrhythmic cells was approximately 60% in the group treated with normal-derived exosomes, similar to the cardiotoxicity model. In contrast, treatment with patient-derived exosomes reduced the proportion of arrhythmic cells to approximately 40%, indicating a superior therapeutic effect in restoring functional stability. Exosomes derived from patient-specific iPSC-CMs effectively alleviate functional abnormalities in a doxorubicin-induced cardiotoxicity model. These findings suggest that patient-derived exosomes retain therapeutic potential and may serve as both a treatment strategy and a source of disease-relevant biomarkers. Exosomes derived from atrial fibrillation patients alleviate arrhythmia by regulating calcium homeostasis