Nicorandil-Pretreated Mesenchymal Stem Cell-Derived Exosomes Facilitate Cardiac Repair After Myocardial Infarction via Promoting Macrophage M2 Polarization by Targeting miR-125a-5p/TRAF6/IRF5 Signaling Pathway

Abstract

Background Exosomes derived from bone marrow mesenchymal stem cells (MSC-exo) have been considered as a promising cell-free therapeutic strategy for ischemic heart disease. Cardioprotective drug pretreatment could be an effective approach to improve the efficacy of MSC-exo. Nicorandil has long been used in clinical practice for cardioprotection. This study aimed to investigate whether the effects of exosomes derived from nicorandil pretreated MSC (MSC NIC -exo) could be enhanced in facilitating cardiac repair after acute myocardial infarction (AMI). Methods MSC NIC -exo and MSC-exo were collected and injected into the border zone of infarcted hearts 30 minutes after coronary ligation in rats. Macrophage polarization was detected 3 days post-infarction, cardiac function as well as histological pathology were measured on the 28th day after AMI. Macrophages were separated from the bone marrow of rats for in vitro model. Exosomal miRNA sequencing was conducted to identify differentially expressed miRNAs between MSC NIC -exo and MSC-exo. MiRNA mimics and inhibitors were transfected to MSCs or macrophages to explore the specific mechanism. Results Compared to MSC-exo, MSC NIC -exo showed superior therapeutic effects on cardiac functional and structural recovery after AMI and markedly elevated the ratio of CD68 + CD206 + / CD68 + cells in infarcted hearts 3 days post-infarction. The notable ability of MSC NIC -exo to promote macrophage M2 polarization was also confirmed in vitro. Exosomal miRNA sequencing and both in vivo and in vitro experiments identified and verified that miR-125a-5p was an effector of the roles of MSC NIC -exo in vivo and in vitro. Furthermore, we found miR-125a-5p promoted macrophage M2 polarization by inhibiting TRAF6/IRF5 signaling pathway. Conclusion This study suggested that MSC NIC -exo could markedly facilitate cardiac repair post-infarction by promoting macrophage M2 polarization by upregulating miR-125a-5p targeting TRAF6/IRF5 signaling pathway, which has great potential for clinical translation.

Dynamic Changes in Ion Channels during Myocardial Infarction and Therapeutic Challenges

“…In addition, pretreatment with nicorandil enhances cardiac repair post acute MI (AMI) by upregulating miRNA-125a-5p in mesenchymal stem cell-derived exosomes (MSC-exo). This upregulation inhibits the TRAF6/IRF5 signaling pathway, promoting M2 macrophage polarization and significantly improving cardiac repair outcomes after AMI [ 144 ]. An analysis of 300 STEMI patients who underwent primary percutaneous coronary intervention (PPCI) for the first time, from January 2020 to December 2022, revealed that thrombus aspiration combined with nicorandil leads to superior improvement in cardiac function [ 145 ].…”

Dual-Omics Approach Unveils Novel Perspective on the Quality Control of Genetically Engineered Exosomes

“…In recent years, the field of nanomedicine has witnessed a remarkable surge in the use of human cell-derived extracellular vesicles, particularly exosomes [ 1 , 2 , 3 , 4 ]. These nano-scale, lipid-encapsulated vesicles (30~150 nm) have emerged as an innovative platform for drug delivery across a wide range of human diseases, including myocardial infarction [ 5 , 6 ], stroke [ 7 , 8 ], infection and inflammation [ 9 , 10 , 11 ], hereditary disorders [ 12 ], cancer [ 13 ], and neurological conditions [ 14 , 15 ]. As natural carriers, exosomes possess unique properties: they are completely biocompatible, capable of penetrating tissues, and can be programmed for precise tissue targeting and drug loading—a significant departure from conventional nanomaterials like silver or gold particles, polymers, and liposomes [ 16 , 17 ].…”