Exosomal MicroRNA Transfer Into Macrophages Mediates Cellular Postconditioning

BACKGROUND:Cardiosphere-derived cells (CDCs) confer cardioprotection in acute myocardial infarction by distinctive macrophage (Mϕ) polarization. Here we demonstrate that CDC-secreted exosomes (CDCexo) recapitulate the cardioprotective effects of CDC therapy known as cellular postconditioning. METHOD...

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Bibliographic Details
Published in:Circulation (New York, N.Y.) N.Y.), 2017-07, Vol.136 (2), p.200-214
Main Authors: de Couto, Geoffrey, Gallet, Romain, Cambier, Linda, Jaghatspanyan, Ervin, Makkar, Nupur, Dawkins, James Frederick, Berman, Benjamin P, Marbán, Eduardo
Format: Article
Language:English
Subjects:
Animals
Cell Polarity - physiology
Cells, Cultured
Exosomes - genetics
Female
Gene Transfer Techniques
Human Umbilical Vein Endothelial Cells
Humans
Macrophages - physiology
MicroRNAs - administration & dosage
MicroRNAs - genetics
Myocardial Infarction - genetics
Myocardial Infarction - prevention & control
Myocytes, Cardiac - physiology
Myocytes, Cardiac - transplantation
Rats
Rats, Inbred WKY
Swine
Swine, Miniature
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Summary:BACKGROUND:Cardiosphere-derived cells (CDCs) confer cardioprotection in acute myocardial infarction by distinctive macrophage (Mϕ) polarization. Here we demonstrate that CDC-secreted exosomes (CDCexo) recapitulate the cardioprotective effects of CDC therapy known as cellular postconditioning. METHODS:Rats and pigs underwent myocardial infarction induced by ischemia/reperfusion before intracoronary infusion of CDCexo, inert fibroblast exosomes (Fbexo; control), or vehicle. Two days later, infarct size was quantified. Macrophages were isolated from cardiac tissue or bone marrow for downstream analyses. RNA sequencing was used to determine exosome content and alterations in gene expression profiles in Mϕ. RESULTS:Administration of CDCexo but not Fbexo after reperfusion reduces infarct size in rat and pig models of myocardial infarction. Furthermore, CDCexo reduce the number of CD68+ Mϕ within infarcted tissue and modify the polarization state of Mϕ so as to mimic that induced by CDCs. CDCexo are enriched in several miRNAs (including miR-146a, miR-181b, and miR-126) relative to Fbexo. Reverse pathway analysis of whole-transcriptome data from CDCexo-primed Mϕ implicated miR-181b as a significant (P=1.3x10) candidate mediator of CDC-induced Mϕ polarization, and PKCδ (protein kinase C δ) as a downstream target. Otherwise inert Fbexo loaded selectively with miR-181b alter Mϕ phenotype and confer cardioprotective efficacy in a rat model of myocardial infarction. Adoptive transfer of PKCδ-suppressed Mϕ recapitulates cardioprotection. CONCLUSIONS:Our data support the hypothesis that exosomal transfer of miR-181b from CDCs into Mϕ reduces PKCδ transcript levels and underlies the cardioprotective effects of CDCs administered after reperfusion.
ISSN:0009-7322
1524-4539
DOI:10.1161/CIRCULATIONAHA.116.024590