Molecular Mechanisms of Exosomes From Human iPSC‐Cardiomyocytes and Mesenchymal Stem Cells in Restoring the Injured Myocardium

BACKGROUND: Exosomes are extracellular vesicles 30 to 150 nm in size, mediating the paracrine effects of mesenchymal stem cells (MSCs) and induced pluripotent stem cell-derived cardiomyocytes (iCMs) when used to restore the injured myocardium. While both MSC- and iCM-derived exosomes (MSC-Exo, iCM-Exo) improve cardiac function, their mechanisms of action remain incompletely understood. This study investigates the shared and distinct effects of iCM-Exo and MSC-Exo in a porcine ischemia-reperfusion injury model. METHODS: iCM-Exo or MSC-Exo into the peri-infarct region. Cardiac function was assessed via MRI at weeks 2 and 4, while transcriptomic sequencing of peri-infarct tissue alongside exosomal cargo were performed to elucidate molecular drivers of exosome influenced, post ischemic modulation of gene expression. RESULTS: Cardiac MRI revealed that iCM-Exo significantly improved left ventricular ejection fraction, myocardial viability, scar size, and ventricular remodeling compared with MSC-Exo and PBS controls. Transcriptomic analysis revealed both shared and distinct gene expression patterns between the treatments. Shared pathways, including extracellular matrix remodeling and neurovascular integration, contributed to baseline cardiac improvement. Distinct pathways in iCM-Exo treatment involved metabolic reorganization and cardiomyocyte-specific processes, while MSC-Exo emphasized structural stabilization and anti-inflammatory responses. CONCLUSIONS: These findings highlight the complementary roles of iCM-Exo and MSC-Exo in myocardial repair with shared pathways contributing to baseline improvement and distinct pathways driving differences in efficacy. Future studies investigating the potential of combinatorial approaches may provide further insights into optimizing the therapeutic outcomes for patients with heart failure.