Cardiosphere-derived cell exosomes delivered IM decrease scarring, halt adverse remodelling and improve LVEF in porcine AMI and CMI. While conceptually attractive as cell-free therapeutic agents for myocardial infarction, exosomes have the disadvantage that IM delivery is necessary.

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=1.3×10−21) 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 PKCδ transcript levels and underlies the cardioprotective effects of CDCs administered after reperfusion.

R e s e a R c h a R t i c l e 3 1 4 8jci.org Volume 125 Number 8 August 2015angioplasty to reopen the occluded coronary artery. After flow has been reestablished, the use of adjunctive therapy can be considered without distraction. Adjunctive cell therapy would require thawing of an allogeneic, off-the-shelf product and preparation for administration, which could introduce a delay of up to 20 minutes. Therefore, in our rat model, we subjected rats to 45 minutes of ischemia, followed by 20 minutes of reperfusion. Cells (or vehicle) were then delivered to the coronary circulation ( Figure 1A). To examine whether cell administration could by adoptive transfer of CDC-primed macrophages. Distinctive changes in macrophage gene expression and function underlie the cardioprotective effects of CDCs.

Cardiosphere‐derived cells (CDCs) reduce myocardial infarct size via secreted extracellular vesicles (CDC‐EVs), including exosomes, which alter macrophage polarization. We questioned whether short non‐coding RNA species of unknown function within CDC‐EVs contribute to cardioprotection. The most abundant RNA species in CDC‐EVs is a Y RNA fragment (EV‐YF1); its relative abundance in CDC‐EVs correlates with CDC potency in vivo. Fluorescently labeled EV‐YF1 is actively transferred from CDCs to target macrophages via CDC‐EVs. Direct transfection of macrophages with EV‐YF1 induced transcription and secretion of IL‐10. When cocultured with rat cardiomyocytes, EV‐YF1‐primed macrophages were potently cytoprotective toward oxidatively stressed cardiomyocytes through induction of IL‐10. In vivo, intracoronary injection of EV‐YF1 following ischemia/reperfusion reduced infarct size. A fragment of Y RNA, highly enriched in CDC‐EVs, alters Il10 gene expression and enhances IL‐10 protein secretion. The demonstration that EV‐YF1 confers cardioprotection highlights the potential importance of diverse exosomal contents of unknown function, above and beyond the usual suspects (e.g., microRNAs and proteins).

Background The pathogenesis of HFpEF is unclear, but fibrosis, inflammation and hypertrophy have been put forth as likely contributors. CDCs are heart-derived cell products with anti-fibrotic and anti-inflammatory properties. Objectives We questioned whether allogeneic rat CDCs might be able to decrease manifestations of HFpEF in hypertensive rats. Methods Starting at 7 weeks of age, Dahl salt-sensitive rats were fed a high-salt diet for 6–7 weeks and randomized to receive intracoronary CDCs or placebo. Dahl rats fed normal chow served as controls. Results High-salt rats developed hypertension, left ventricular (LV) hypertrophy and diastolic dysfunction, without impairment of ejection fraction. Four weeks after treatment, diastolic dysfunction resolved in CDC-treated rats but not in placebo. The improved LV relaxation was associated with lower LV end-diastolic pressure, decreased lung congestion and enhanced survival in CDC-treated rats. Histology and echocardiography revealed no decrease in cardiac hypertrophy after CDC treatment, consistent with the finding of sustained, equally-elevated blood pressure in CDC- and placebo-treated rats. Nevertheless, CDC treatment decreased LV fibrosis and inflammatory infiltrates. Serum inflammatory cytokines were likewise decreased after CDC treatment. Whole-transcriptome analysis revealed major HFpEF-related, CDC-reversed changes in numerous transcripts, including many involved in inflammation and/or fibrosis. Conclusion CDCs normalized LV relaxation and LV diastolic pressure while improving survival in a rat model of HFpEF. The benefits of CDCs occurred despite persistent hypertension and cardiac hypertrophy. By selectively reversing inflammation and fibrosis, CDCs may be beneficial in the treatment of HFpEF.