Exosomes derived from human umbilical cord mesenchymal stem cells can reverse ventricular remodeling and improve long-term cardiac function after acute myocardial infarction

Background: Acute myocardial infarction (AMI) is the most common ischemic heart disease with high morbidity and high mortality. Although the treatment of AMI is constantly developing, ischemia-reperfusion (I/R) injury remains a complex problem. In recent years, human umbilical cord-derived mesenchymal stem cell-derived exosomes (hUC-MSC-EXO) have been shown to alleviate related damages. However, the long-term effects, safety, and mechanism of action have not yet been fully explored. Methods: We constructed human umbilical cord-derived mesenchymal stem cell-derived engineered exosomes. We compared the short-term and long-term protective abilities of engineered exosomes on myocardium during I/ R in cardiomyocytes and rat models, and determined their long-term safety. At the same time, key pathways and genes were predicted through exosome sequencing. Results: hUC-MSC-EXO significantly reduced apoptosis, oxidative stress, and inflammation in both in vitro and in vivo models. In I/R rats, IMTP-EXO demonstrated superior cardioprotective effects, reducing myocardial fibrosis and improving left ventricular function compared to controls. Long-term studies showed enhanced ejection fraction (EF) and fractional shortening (FS) and reduced left ventricular end-diastolic dimensions (LVEDD). Fluorescence imaging revealed higher exosome accumulation in ischemic hearts. Genes related to cardiovascular diseases were obtained through cross-comparison of multiple databases. GO analysis revealed that protein binding was the most highly enriched term. KEGG analysis showed that these genes were primarily involved in apoptosis and the PI3K-Akt signaling pathways. The PPI network showed that TP53, TLR4, EGFR, MAPK3, and GJA1 are central genes of heart I/R injury. GJA1, HMGB1, and PTEN are considered to be key genes by comparing to the comparative toxicogenomic database (CTD). Conclusions: This study demonstrates that hUC-MSC-derived exosomes, especially IMTP-EXO, are safe, feasible, and effective for reversing ventricular remodeling and improving cardiac function in rat MI models. GJA1, HMGB1, and PTEN may be the key genes associated with myocardial I/R injury. These findings provide critical insights for translating hUC-MSC-EXO into clinical applications for treating myocardial I/R injuries.