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Depletion and Reconstitution of Macrophages in Mice
Published on: August 1, 2012
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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
Summary
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.
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