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.