Abstract
Background:
Mesenchymal stem cell-derived exosomes (MSC-EXO) have emerged as novel therapeutic strategies for myocardial infarction (MI). However, many questions remain untouched and unanswered regarding their roles in myocardial fibrosis. This study aimed to probe the therapeutic effects of MSC-EXO on myocardial fibrosis after MI and possible mechanisms.
Methods:
Myocardial tissues were obtained from MI rats, and myocardial cell viability, fibrosis, apoptosis, and epithelial-mesenchymal transition (EMT) were detected by immunohistochemistry, Masson's staining, TUNEL, and western blot. Bone marrow-derived MSCs and corresponding EXO were identified, and cardiac function were detected after treatment of MSC-EXO. Bioinformatics analysis and ChIP assay were conducted to detect the downstream genes of EZH2. EZH2 was upregulated alone or with HMGA2 overexpression in myocardial tissues of MI rats upon MSC-EXO treatment, and PI3K/AKT pathway activity in myocardial tissues was detected using western blot.
Results:
The proliferative activity in myocardial tissues of MI rats was significantly decreased, along with accentuated fibrosis, increased collagen volume and EMT. MSC-EXO treatment resulted in partial restoration of cardiac function and reduced EZH2 expression in the myocardium of rats. EZH2 inhibited HMGA2 expression by increasing the H3K27me3 modification. PI3K/AKT pathway was altered under the influence of the EZH2/HMGA2 axis. EZH2 inhibited the effect of MSC-EXO on the recovery of cardiac function and accelerated fibrosis, while HMGA2 reversed the effect of EZH2 to reduce fibrosis and enhance cardiac function.
Conclusion:
MSC-EXO alleviated fibrosis in MI rats via inhibition of EZH2, whereas EZH2 inhibited HMGA2 expression and impaired the PI3K/AKT pathway.