Durable Benefits of Cellular Postconditioning: Long‐Term Effects of Allogeneic Cardiosphere‐Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction

Tseliou, Eleni; Couto, Geoffrey de; Gallet, Romain; Malliaras, Konstantinos; Yee, Kristine; Kreke, Michelle; Valle, Ileana; Smith, Rachel; Middleton, Ryan; Ho, Chak Sum; Dharmakumar, Rohan; Li, Debiao; Makkar, Raj; Fukuda, Keiichi; Marbán, Linda; Marbán, Eduardo

doi:10.1161/jaha.115.002796

Cited by 35 publications

(41 citation statements)

References 47 publications

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“…12 , and are readily taken up by numerous cell types including macrophages 13 , fibroblasts 14 , and endothelial cells 15 . Here, we extend our recent work on cellular postconditioning by CDCs 16–18 by identifying CDC exosomes (CDC exo ) 19 as key elements of the cellular secretome which confer cardioprotection in MI. We further demonstrate that miR-181b within CDC exo is a critical mediator of macrophage polarization in vitro and cardioprotection in vivo .…”

Section: Introductionmentioning

confidence: 58%

Exosomal MicroRNA Transfer Into Macrophages Mediates Cellular Postconditioning

et al. 2017

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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.

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Section: Introductionmentioning

confidence: 58%

Exosomal MicroRNA Transfer Into Macrophages Mediates Cellular Postconditioning

et al. 2017

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“…It its interesting to note that LV structure and function were preserved in CDC-treated spontaneously hypertensive rats at 28 days post-AMI in comparison with rats that had received phosphate-buffered saline (Figure 2), verifying that the effects are durable (as the Marbán laboratory had shown in another pig study). 90 …”

Section: Cellular Postconditioningmentioning

confidence: 99%

Is Cardioprotection Dead?

Lefer

Marbán

2017

Circulation

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For >4 decades, the holy grail in the treatment of acute myocardial infarction has been the mitigation of lethal injury. Despite promising initial results and decades of investigation by the cardiology research community, the only treatment with proven efficacy is early reperfusion of the occluded coronary artery. The remarkable record of failure has led us and others to wonder if cardioprotection is dead. The path to translation, like the ascent to Everest, is certainly littered with corpses. We do, however, highlight a therapeutic principle that provides a glimmer of hope: cellular postconditioning. Administration of cardiosphere-derived cells after reperfusion limits infarct size measured acutely, while providing long-term structural and functional benefits. The recognition that cell therapy may be cardioprotective, and not just regenerative, merits further exploration before we abandon the pursuit entirely.

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“…When allogeneic cells were administered immediately after reperfusion in porcine infarct models, favorable remote zone remodeling was seen after mesenchymal precursor cells (MPCs) 6 and CBSCs 4 from the present study. Directionally similar results in myocyte area were found after allogeneic CDCs administered after reperfusion although myocyte nuclear density was not reported 9 . In contrast, several studies utilizing regional cell administration several weeks after MI have demonstrated reductions in infarct size but failed to show major effects on remote zone myocyte hypertrophy 10–12 .…”

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confidence: 56%

“…Thus, it seems plausible that the mechanism of action of CBSCs may actually reflect acute modulation of the host inflammatory response to myocardial injury in the ischemic as well as remote region of the heart. Further studies will be required to investigate this but similar immune modulatory actions have already been identified for CDCs 9 and MSCs 13 . The second relates to the time course of the functional improvement in CBSC-treated animals.…”

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confidence: 66%