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Exosomal MicroRNA Transfer Into Macrophages Mediates Cellular Postconditioning

Geoffrey de Couto1, Romain Gallet1, Linda Cambier1

  • 1From Cedars-Sinai Heart Institute, Los Angeles, CA (G.d.C., R.G., L.C., E.J., N.M., J.F.D., B.P.B., E.M.); and Cedars-Sinai Center for Bioinformatics and Functional Genomics, Los Angeles, CA (B.P.B.).

Circulation
|April 16, 2017
PubMed

Insights

Cardiosphere-derived exosomes (CDCexo) reduce heart attack damage by reprogramming macrophages. Exosomal miR-181b mediates this effect by targeting PKCδ, offering a novel therapeutic strategy for myocardial infarction.

Area of Science:

  • Cardiovascular Biology
  • Cellular Therapeutics
  • Exosome Biology

Background:

  • Cardiosphere-derived cells (CDCs) protect the heart in acute myocardial infarction through macrophage polarization.
  • CDC-secreted exosomes (CDCexo) are investigated for their potential to replicate the cardioprotective effects of CDC therapy, known as cellular postconditioning.

Purpose of the Study:

  • To determine if CDC-secreted exosomes (CDCexo) can recapitulate the cardioprotective effects of cardiosphere-derived cells (CDCs) in myocardial infarction.
  • To elucidate the underlying molecular mechanisms, particularly the role of microRNAs (miRNAs) and macrophage polarization.

Main Methods:

  • Myocardial infarction was induced in rat and pig models via ischemia/reperfusion.
  • Intracoronary infusion of CDCexo, fibroblast exosomes (Fbexo), or vehicle was administered.
  • Infarct size, macrophage populations (CD68+), Mϕ polarization, exosome miRNA content, and Mϕ gene expression profiles (RNA sequencing) were analyzed.

Main Results:

  • CDCexo administration significantly reduced infarct size in both rat and pig models, unlike Fbexo.
  • CDCexo decreased CD68+ Mϕ in infarcted tissue and altered Mϕ polarization.
  • miR-181b within CDCexo was identified as a key mediator of Mϕ polarization, targeting PKCδ; engineered Fbexo with miR-181b mimicked these effects.

Conclusions:

  • Exosomal transfer of miR-181b from CDCs to macrophages underlies the cardioprotective effects observed after reperfusion.
  • This mechanism involves the reduction of PKCδ transcript levels, highlighting a novel therapeutic pathway for myocardial infarction treatment.
Abstract

Keywords:
cardioprotectionexosomemacrophagemiRNAmyocardial infarction

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