title: Exosomes as critical agents of cardiac regeneration triggered by cell therapy.
abstract: The CADUCEUS trial of cardiosphere-derived cells (CDCs) has shown that it may be possible to regenerate injured heart muscle previously thought to be permanently scarred. The mechanisms of benefit are known to be indirect, but the mediators have yet to be identified. Here we pinpoint exosomes secreted by human CDCs as critical agents of regeneration and cardioprotection. CDC exosomes inhibit apoptosis and promote proliferation of cardiomyocytes, while enhancing angiogenesis. Injection of exosomes into injured mouse hearts recapitulates the regenerative and functional effects produced by CDC transplantation, whereas inhibition of exosome production by CDCs blocks those benefits. CDC exosomes contain a distinctive complement of microRNAs, with particular enrichment of miR-146a. Selective administration of a miR-146a mimic reproduces some (but not all) of the benefits of CDC exosomes. The findings identify exosomes as key mediators of CDC-induced regeneration, while highlighting the potential utility of exosomes as cell-free therapeutic candidates.
authors.affiliation: Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Ahmed Gamal-Eldin
authors.initials: AG
authors.lastname: Ibrahim
authors.affiliation: Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Cheng
authors.affiliation: Heart Institute, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Marbán
mesh_terms: D000418:Albumins / Q000494:pharmacology; D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology; D002454:Cell Differentiation; D049109:Cell Proliferation; D064987:Cell- and Tissue-Based Therapy; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055354:Exosomes / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D009203:Myocardial Infarction / Q000628:therapy / Q000662:veterinary; D032383:Myocytes, Cardiac / Q000166:cytology / Q000637:transplantation; D018919:Neovascularization, Physiologic; D011091:Polyesters / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration
chemical_list: D000418:Albumins; D000814:Aniline Compounds; D001597:Benzylidene Compounds; C468773:GW 4869; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; C522044:PB-127 compound; D011091:Polyesters