Mesenchymal stromal cell-derived exosomes attenuate myocardial ischaemia-reperfusion injury through miR-182-regulated macrophage polarization

Abstract

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.

Macrophage M2 polarization induced by exosomes from adipose-derived stem cells contributes to the exosomal proangiogenic effect on mouse ischemic hindlimb

“…The administration of the CSF-1R inhibitor BLZ945 affects the efficacy of exosomes in the ischemic hindlimb. A recent study demonstrated that exosomes from bone marrow-derived MSCs attenuate myocardial ischemiareperfusion injury through macrophage polarization, which is consistent with our observations [34]. miRNAs in exosomes play an essential role in mediating cell-cell communication.…”

Message in a Bottle: Upgrading Cardiac Repair into Rejuvenation

“…EVs obtained from AD-MSCs have been demonstrated protection of the myocardium against I/R injury via the Wnt/b-catenin signalling pathway [183]. As a matter of fact, the remarkably strong immunosuppressive effect of both BM-and AD-MSC-EVs on T cell activation and macrophage polarisation has been documented as one of their major beneficial effects [184][185][186]. Increasing evidence has indicated that the EV microRNA (miRNA) content as one of their most likely paracrine mechanism(s) of action.…”

Ultrafiltration Segregates Tissue Regenerative Stimuli Harboured Within and Independent of Extracellular Vesicles

“…Losordo and colleagues demonstrated human CD34+ hematopoietic progenitors generated exosomes in vitro that transferred miR-126-3p to reduce SPRED1 mRNA in murine endothelial cells in vivo, in return enhancing hindlimb revascularization and recovery from ischemia 80 . The secretome of MSC is also known to influence the infiltration hematopoietic cells following tissue injury, including the promotion of a pro-regenerative M2 macrophage differentiation via the transfer of nucleic acid cargo [81][82][83] . Thus, future studies will need to determine whether cargo enriched in EV+ CM can influence the phenotypic and tissue regenerative properties of infiltrating hematopoietic, stromal, or progenitor cells.…”