Journal
CARDIOVASCULAR RESEARCH
Volume 115, Issue 7, Pages 1205-1216Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvz040
Keywords
Myocardial ischaemia/reperfusion injury; Mesenchymal stromal cells; Exosomes; Macrophage polarization; MicroRNA
Categories
Funding
- Natural Science Foundation of China [81470371, 81870358]
- Jiangsu Provincial Key Medical Discipline [ZDXKB2016013]
- Key Projects of Science and Technology of Jiangsu Province [BE2016607]
- Jiangsu Provincial Medical Youth Talent [QNRC2016033, Q201610]
- Programs of the Science Foundation in Nanjing [ZKX17011, YKK15061, 201605015]
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Aims Mesenchymal stromal cells ( MSCs) gradually become attractive candidates for cardiac inflammation modulation, yet understanding of the mechanism remains elusive. Strikingly, recent studies indicated that exosomes secreted by MSCs might be a novel mechanism for the beneficial effect of MSCs transplantation after myocardial infarction. We therefore explored the role of MSC-derived exosomes ( MSC-Exo) in the immunomodulation of macrophages after myocardial ischaemia/reperfusion ( I/R) and its implications in cardiac injury repair. Methods and results Exosomes were isolated from the supernatant of MSCs using gradient centrifugation method. Administration of MSC-Exo to mice through intramyocardial injection after myocardial I/R reduced infarct size and alleviated inflammation level in heart and serum. Systemic depletion of macrophages with clodronate liposomes abolished the curative effects of MSC-Exo. MSC-Exo modified the polarization of M1 macrophages to M2 macrophages both in vivo and in vitro. miRNA sequencing of MSC-Exo and bioinformatics analysis implicated miR-182 as a potent candidate mediator of macrophage polarization and toll-like receptor 4 ( TLR4) as a downstream target. Diminishing miR-182 in MSC-Exo partially attenuated its modulation of macrophage polarization. Likewise, knock down of TLR4 also conferred cardioprotective efficacy and reduced inflammation level in a mouse model of myocardial I/R. Conclusion Our data indicate that MSC-Exo attenuates myocardial I/R injury in mice via shuttling miR-182 that modifies the polarization status of macrophages. This study sheds new light on the application of MSC-Exo as a potential therapeutic tool for myocardial I/R injury.
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