![Sample our Engineering & Technology journals, sign in here to start your access, latest two full volumes FREE to you for 14 days]({"type":"image" , "src" : "/sda/5933/TOC-Subject-Sample-2021-Engineering-Tech.jpg"})
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 (MSCNIC-exo) could be enhanced in facilitating cardiac repair after acute myocardial infarction (AMI).
Methods
MSCNIC-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 MSCNIC-exo and MSC-exo. MiRNA mimics and inhibitors were transfected to MSCs or macrophages to explore the specific mechanism.
Results
Compared to MSC-exo, MSCNIC-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 MSCNIC-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 MSCNIC-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 MSCNIC-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.
Graphical Abstract
Abbreviations
MSC, Mesenchymal stem cell; SD, Sprague–Dawley; NIC, Nicorandil; AMI, Acute myocardial infarction; BMDM, Bone marrow-derived macrophage; CSF, Colony stimulating factor; LPS, Lipopolysaccharide; IFN-γ, Interferon—γ; IL, Interleukin; Mrc1, Mannose Receptor C Type 1; Tgfb1, Transforming growth factor beta 1; Vegfa, Vascular Endothelial Growth Factor A; Arg1, Arginase 1; TRAF6, TNF receptor associated factor 6; IRF5, Interferon regulatory factor 5; miRNA, MicroRNA; PBS, Phosphate-buffered saline; TEM, Transmission electron microscope; NTA, Nanoparticle tracking analysis; LVEF, Left ventricular ejection fraction; LVFS, Left ventricular fractional shortening; LVEDV, Left ventricular end-diastolic volume; LVESV, Left ventricular end-systolic volume; HE, Hemoxylin-eosin; NC, Negative control; qRT-PCR, Quantitative reverse transcription-polymerase chain reaction; IL-4R, IL-4 receptor.
Data Sharing Statement
The datasets generated and analyzed in the present study are available via the Gene Expression Omnibus under accession code GSE229889, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE229889.
Ethics Approval and Consent to Participate
Animal protocols were performed with approval of the Experimental Animals Ethics Committee of Fuwai Hospital (FW-2022-0032).
Disclosure
The authors declare that they have no competing interests in this work.