Exosomes are served as substitutes for stem cell therapy, playing important roles in mediating heart repair during myocardial infarction injury. Evidence have indicated that lipopolysaccharide (LPS) pre‐conditioning bone marrow‐derived mesenchymal stem cells (BMSCs) and their secreted exosomes promote macrophage polarization and tissue repair in several inflammation diseases; however, it has not been fully elucidated in myocardial infarction (MI). This study aimed to investigate whether LPS‐primed BMSC‐derived exosomes could mediate inflammation and myocardial injury via macrophage polarization after MI. Here, we found that exosomes derived from BMSCs, in both Exo and L‐Exo groups, increased M2 macrophage polarization and decreased M1 macrophage polarization under LPS stimulation, which strongly depressed LPS‐dependent NF‐κB signalling pathway and partly activated the AKT1/AKT2 signalling pathway. Compared with Exo, L‐Exo had superior therapeutic effects on polarizing M2 macrophage in vitro and attenuated the post‐infarction inflammation and cardiomyocyte apoptosis by mediating macrophage polarization in mice MI model. Consequently, we have confidence in the perspective that low concentration of LPS pre‐conditioning BMSC‐derived exosomes may develop into a promising cell‐free treatment strategy for clinical treatment of MI.

Stem cell therapy can be used to repair and regenerate damaged hearts tissue; nevertheless, the low survival rate of transplanted cells limits their therapeutic efficacy. Recently, it has been proposed that exosomes regulate multiple cellular processes by mediating cell survival and communication among cells. The following study investigates whether injured cardiomyocytes-derived exosomes (cardiac exosomes) affect the survival of transplanted bone marrow mesenchymal stem cells (BMSCs) in infarcted heart. To mimic the harsh microenvironment in infarcted heart that the cardiomyocytes or transplanted BMSCs encounter in vivo, cardiomyocytes conditioned medium and cardiac exosomes collected from H2O2-treated cardiomyocytes culture medium were cultured with BMSCs under oxidative stress in vitro. Cardiomyocytes conditioned medium and cardiac exosomes significantly accelerated the injury of BMSCs induced by H2O2; increased cleaved caspase-3/caspase-3 and apoptotic percentage, and decreased the ratio of Bcl-2/Bax and cell viability in those cells. Next, we explored the role of cardiac exosomes in the survival of transplanted BMSCs in vivo by constructing a Rab27a knockout (KO) mice model by a transcription activator-like effector nuclease (TALEN) genome-editing technique; Rab27a is a family of GTPases, which has critical role in secretion of exosomes. Male mouse GFP-modified BMSCs were implanted into the viable myocardium bordering the infarction in Rab27a KO and wild-type female mice. The obtained results showed that the transplanted BMSCs survival in infarcted heart was increased in Rab27a KO mice by the higher level of Y-chromosome Sry DNA, GFP mRNA, and the GFP fluorescence signal intensity. To sum up, these findings revealed that the injured cardiomyocytes-derived exosomes accelerate transplanted BMSCs injury in infarcted heart, thus highlighting a new mechanism underlying the survival of transplanted cells after myocardial infarction.

Atherosclerosis is regarded as a chronic progressive inflammatory disease and is a basic pathophysiological process in coronary artery disease which is life threatening in clinic. The formation of foam cell plays a key role in the pathogenesis of atherosclerosis. OxLDL is a significant factor in progression of coronary artery disease. Our studies have demonstrated that USP14 promotes cancer development and mediates progression of cardiac hypertrophy and LPS‐induced inflammation. However, the underlying mechanism of USP14 is unknown. In this study, we found that the inhibition of USP14 significantly suppressed the oxLDL uptake, subsequently decreased the foam cell formation. Surprisingly, USP14 has an effect on the expression of CD36 but not SR‐A, ABCA1, Lox‐1, ABCG1 and SR‐Bl. Furthermore, USP14 stabilizes CD36 protein via cleaving the ubiquitin chain on CD36. Blocking CD36 activation using antibody‐dependent blocking assay remarkably attenuated the function of USP14 on the formation of foam cell. In summary, our results suggested that the inhibition of USP14 decreases foam cell formation by down‐regulating CD36‐mediated lipid uptake and provides a potential therapeutic target for atherosclerosis.