Abstract
BackgroundApplication of mesenchymal stem cell-derived exosomes (MSC-EXO) has emerged as a novel therapeutic strategy for myocardial infarction (MI). Our previous study showed that pretreatment with hemin, a potent heme oxygenase-1 (HO-1) inducer, enhanced the cardioprotective effects of MSCs in a mouse model of MI. This study aimed to investigate the therapeutic effects of EXO derived from hemin-pretreated MSCs (Hemin-MSC-EXO) in MI and explore the potential mechanisms.MethodsMSC-EXO and Hemin-MSC-EXO were collected and characterized. MSC-EXO and Hemin-MSC-EXO were intramuscularly injected into the peri-infarct region in a mouse model of MI. Heart function of mice was assessed by echocardiography. The mitochondrial morphology of neonatal mice cardiomyocytes (NMCMs) under serum deprivation and hypoxic (SD/H) conditions was examined by Mitotracker staining. The cellular senescence of NMCMs was determined by senescence-associated-β-galactosidase assay. A loss-of-function approach was adopted to determine the role of Hemin-MSC-exosomal-miR-183-5p in the regulation of cardiomyocyte senescenceResultsEXO were successfully isolated from the supernatant of MSCs and Hemin-pretreated MSCs. Compared with MSC-EXO, injection of Hemin-MSC-EXO significantly improved cardiac function and reduced fibrosis. Both MSC-EXO and Hemin-MSC-EXO ameliorated cardiomyocyte senescence and mitochondrial fission in vitro and in vivo, and the latter exhibited better protective effects. MicroRNA sequencing revealed a higher level of miR-183-5p in Hemin-MSC-EXO than in MSC-EXO. MiR-183-5p knockdown partially abrogated the protective effects of Hemin-MSC-EXO in attenuating mitochondrial fission and cellular senescence of cardiomyocytes induced by SD/H. High mobility group box-1 (HMGB1) abundance was lower in Hemin-MSC-EXO-treated than MSC-EXO-treated mouse hearts, and HMGB1 was identified as one of the potential target genes of miR-183-5p. Mechanistically, Hemin-MSC-EXO inhibited SD/H-induced cardiomyocyte senescence partially by delivering miR-183-5p into recipient cardiomyocytes via regulation of the HMGB1/ERK pathway. Furthermore, knockdown of miR-183-5p reduced the Hemin-MSC-EXO-mediated cardioprotective effects in a mouse model of MI.ConclusionOur results reveal that Hemin-MSC-EXO are superior to MSC-EXO in treating MI. Exosomal miR-183-5p mediates, at least partially, the cardioprotective effects of Hemin-MSC-EXO by inhibiting cardiomyocyte senescence via regulation of the HMGB1/ERK pathway. This study highlights that MSC-EXO have high translational value in repairing cardiac dysfunction following infarction.Graphic abstract
Highlights
Myocardial infarction (MI) is the leading cause of morbidity and mortality worldwide
Our results reveal that Hemin-mesenchymal stem cell-derived exosomes (MSC-EXO) are superior to MSC-EXO in treating myocardial infarction (MI)
Transmission electron microscopy (TEM) imaging analysis demonstrated that both MSC-EXO and Hemin-MSC-EXO displayed a typical cup-shaped morphology with a double-layer membrane structure (Fig. 1A)
Summary
Myocardial infarction (MI) is the leading cause of morbidity and mortality worldwide. Senescent cells secrete a senescenceassociated secretory phenotype (SASP) consisting of various proinflammatory cytokines and growth factors. Senescent cardiomyocytes partially impair the function of non-myocytes, including endothelial cells and fibroblasts, via SASP factors, accelerating heart injury [8]. Treatment with the senolytic drug navitoclax has been shown to clear the cardiomyocyte senescence induced by ischemia–reperfusion in mice and significantly improve heart function by attenuating pro-inflammatory and profibrotic SASP, suggesting that clearance of senescent cardiomyocytes can improve heart function following infarction [9]. The precise molecular mechanisms underlying cardiomyocyte senescence in the heart following infarction remain unclear. Application of mesenchymal stem cell-derived exosomes (MSC-EXO) has emerged as a novel therapeutic strategy for myocardial infarction (MI). This study aimed to investigate the therapeutic effects of EXO derived from hemin-pretreated MSCs (Hemin-MSC-EXO) in MI and explore the potential mechanisms
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