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Exosomal MicroRNA Transfer Into Macrophages Mediates Cellular Postconditioning.

ABSTRACT: BACKGROUND:Cardiosphere-derived cells (CDCs) confer cardioprotection in acute myocardial infarction by distinctive macrophage (M?) 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 M?. 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+ M? within infarcted tissue and modify the polarization state of M? 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 M? implicated miR-181b as a significant (P=1.3x10-21) candidate mediator of CDC-induced M? polarization, and PKC? (protein kinase C ?) as a downstream target. Otherwise inert Fbexo loaded selectively with miR-181b alter M? phenotype and confer cardioprotective efficacy in a rat model of myocardial infarction. Adoptive transfer of PKC?-suppressed M? recapitulates cardioprotection. CONCLUSIONS:Our data support the hypothesis that exosomal transfer of miR-181b from CDCs into M? reduces PKC? transcript levels and underlies the cardioprotective effects of CDCs administered after reperfusion.

SUBMITTER: de Couto G

PROVIDER: S-EPMC5505791 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Exosomal MicroRNA Transfer Into Macrophages Mediates Cellular Postconditioning.

de Couto Geoffrey G Gallet Romain R Cambier Linda L Jaghatspanyan Ervin E Makkar Nupur N Dawkins James Frederick JF Berman Benjamin P BP Marbán Eduardo E

Circulation 20170414 2

<h4>Background</h4>Cardiosphere-derived cells (CDCs) confer cardioprotection in acute myocardial infarction by distinctive macrophage (Mϕ) polarization. Here we demonstrate that CDC-secreted exosomes (CDC<sub>exo</sub>) recapitulate the cardioprotective effects of CDC therapy known as cellular postconditioning.<h4>Methods</h4>Rats and pigs underwent myocardial infarction induced by ischemia/reperfusion before intracoronary infusion of CDC<sub>exo</sub>, inert fibroblast exosomes (Fb<sub>exo</sub ...[more]

PMID: 28411247

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Project description:RATIONALE:The promising clinical benefits of delivering human mesenchymal stem cells (hMSCs) for treating heart disease warrant a better understanding of underlying mechanisms of action. hMSC exosomes increase myocardial contractility; however, the exosomal cargo responsible for these effects remains unresolved. OBJECTIVE:This study aims to identify lead cardioactive hMSC exosomal microRNAs to provide a mechanistic basis for optimizing future stem cell-based cardiotherapies. METHODS AND RESULTS:Integrating systems biology and human engineered cardiac tissue (hECT) technologies, partial least squares regression analysis of exosomal microRNA profiling data predicted microRNA-21-5p (miR-21-5p) levels positively correlate with contractile force and calcium handling gene expression responses in hECTs treated with conditioned media from multiple cell types. Furthermore, miR-21-5p levels were significantly elevated in hECTs treated with the exosome-enriched fraction of the hMSC secretome (hMSC-exo) versus untreated controls. This motivated experimentally testing the human-specific role of miR-21-5p in hMSC-exo-mediated increases of cardiac tissue contractility. Treating hECTs with miR-21-5p alone was sufficient to recapitulate effects observed with hMSC-exo on hECT developed force and expression of associated calcium handling genes (eg, SERCA2a and L-type calcium channel). Conversely, knockdown of miR-21-5p in hMSCs significantly diminished exosomal procontractile and associated calcium handling gene expression effects on hECTs. Western blots supported miR-21-5p effects on calcium handling gene expression at the protein level, corresponding to significantly increased calcium transient amplitude and decreased decay time constant in comparison to miR-scramble control. Mechanistically, cotreating with miR-21-5p and LY294002, a PI3K inhibitor, suppressed these effects. Finally, mathematical simulations predicted the translational capacity for miR-21-5p treatment to restore calcium handling in mature ischemic adult human cardiomyocytes. CONCLUSIONS:miR-21-5p plays a key role in hMSC-exo-mediated effects on cardiac contractility and calcium handling, likely via PI3K signaling. These findings may open new avenues of research to harness the role of miR-21-5p in optimizing future stem cell-based cardiotherapies.

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Exosomal MicroRNA Transfer Into Macrophages Mediates Cellular Postconditioning.

Publications

Exosomal MicroRNA Transfer Into Macrophages Mediates Cellular Postconditioning.

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