Exosomal microRNA Transfer into Macrophages Mediates Cellular Postconditioning
BACKGROUND: Cardiosphere-derived cells (CDCs) confer cardioprotection in acute myocardial infarction (MI) via 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 MI induced by ischemia-reperfusion prior to 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 MI. 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=1.3x10-21) candidate mediator of CDC-induced MΦ polarization and protein kinase C δ (PKCδ) as a downstream target. Otherwise-inert Fbexo loaded selectively with miR-181b alter MΦ phenotype and confer cardioprotective efficacy in a rat model of MI. 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 PKC δ transcript levels and underlies the cardioprotective effects of CDCs administered after reperfusion.
- Received July 20, 2016.
- Revision received March 3, 2017.
- Accepted March 30, 2017.