EZH2 mitigates the cardioprotective effects of mesenchymal stem cell-secreted exosomes against infarction via HMGA2-mediated PI3K/AKT signaling

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.

Advances in the study of exosomes derived from mesenchymal stem cells and cardiac cells for the treatment of myocardial infarction

“…2 ). For instance, regulatory RNAs in BMSC-derived exosomes can influence the phosphatidylinositol3-kinase/ protein kinase B (PI3K/AKT) pathway to attenuate cardiac fibrosis after MI and myocardial injury after hypoxia [ 48 , 49 ]. Additionally, several miRNAs can regulate the C-Jun N-terminal kinase (JNK) pathway, which is a key regulatory pathway of apoptosis.…”

Engineered exosomes for tissue regeneration: from biouptake, functionalization and biosafety to applications

“…226 MSC-Exo has been shown to alleviate fibrosis in MI rats by inhibiting EZH2. 227 HIF-1α overexpressing exosomes to maintain cardiac function by promoting neointima formation and inhibiting fibrosis in a rat model of myocardial infarction. 228 There is substantial evidence that engineered exosomes can perform more effectively in combination with other biomaterials.…”

Epigenetic regulation in myocardial infarction: Non-coding RNAs and exosomal non-coding RNAs

“…In ischemic heart disease (IHD), elevated EZH2 epigenetically represses cardiac sodium channel NaV1.5, which is one of the underlying mechanisms of arrhythmias in IHD patients ( 51 ). Recently, Jiao et al done a study to investigate the therapeutic effects of mesenchymal stem cell-secreted exosomes (MSC-EXO) on myocardial fibrosis after MI ( 52 ). They found EZH2 alleviates the cardioprotective effects of MSC-EXO in MI rats through inhibiting HMGA2 (High mobility group AT-Hook 2) expression and disrupting the PI3K/AKT pathway ( 52 ).…”

“…Recently, Jiao et al done a study to investigate the therapeutic effects of mesenchymal stem cell-secreted exosomes (MSC-EXO) on myocardial fibrosis after MI ( 52 ). They found EZH2 alleviates the cardioprotective effects of MSC-EXO in MI rats through inhibiting HMGA2 (High mobility group AT-Hook 2) expression and disrupting the PI3K/AKT pathway ( 52 ).…”