title: Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction.
abstract: OBJECTIVE
  Recent evidence suggests that cardiac progenitor cells (CPCs) may improve cardiac function after injury. The underlying mechanisms are indirect, but their mediators remain unidentified. Exosomes and other secreted membrane vesicles, hereafter collectively referred to as extracellular vesicles (EVs), act as paracrine signalling mediators. Here, we report that EVs secreted by human CPCs are crucial cardioprotective agents.
  
  
  RESULTS
  CPCs were derived from atrial appendage explants from patients who underwent heart valve surgery. CPC-conditioned medium (CM) inhibited apoptosis in mouse HL-1 cardiomyocytic cells, while enhancing tube formation in human umbilical vein endothelial cells. These effects were abrogated by depleting CM of EVs. They were reproduced by EVs secreted by CPCs, but not by those secreted by human dermal fibroblasts. Transmission electron microscopy and nanoparticle tracking analysis showed most EVs to be 30-90 nm in diameter, the size of exosomes, although smaller and larger vesicles were also present. MicroRNAs most highly enriched in EVs secreted by CPCs compared with fibroblasts included miR-210, miR-132, and miR-146a-3p. miR-210 down-regulated its known targets, ephrin A3 and PTP1b, inhibiting apoptosis in cardiomyocytic cells. miR-132 down-regulated its target, RasGAP-p120, enhancing tube formation in endothelial cells. Infarcted hearts injected with EVs from CPCs, but not from fibroblasts, exhibited less cardiomyocyte apoptosis, enhanced angiogenesis, and improved LV ejection fraction (0.8 ± 6.8 vs. -21.3 ± 4.5%; P < 0.05) compared with those injected with control medium.
  
  
  CONCLUSIONS
  EVs are the active component of the paracrine secretion by human CPCs. As a cell-free approach, EVs could circumvent many of the limitations of cell transplantation.
authors.affiliation: Laboratory of Molecular and Cellular Cardiology, Departments of Cardiology and Heart Surgery, Fondazione Cardiocentro Ticino, Via Tesserete 48, CH-6900 Lugano, Switzerland lucio.barile@cardiocentro.org giuseppe.vassalli@cardiocentro.org.
authors.forename: Lucio
authors.initials: L
authors.lastname: Barile
authors.affiliation: Laboratory of Medical Science, Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Lionetti
authors.affiliation: Laboratory of Molecular and Cellular Cardiology, Departments of Cardiology and Heart Surgery, Fondazione Cardiocentro Ticino, Via Tesserete 48, CH-6900 Lugano, Switzerland.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Cervio
authors.affiliation: Laboratory of Medical Science, Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Matteucci
authors.affiliation: 'Victor' Babes National Institute of Pathology, Bucharest, Romania.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Gherghiceanu
authors.affiliation: 'Victor' Babes National Institute of Pathology, Bucharest, Romania.
authors.forename: Laurentiu M
authors.initials: LM
authors.lastname: Popescu
authors.affiliation: Laboratory of Molecular and Cellular Cardiology, Departments of Cardiology and Heart Surgery, Fondazione Cardiocentro Ticino, Via Tesserete 48, CH-6900 Lugano, Switzerland.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Torre
authors.affiliation: Laboratory of Molecular and Cellular Cardiology, Departments of Cardiology and Heart Surgery, Fondazione Cardiocentro Ticino, Via Tesserete 48, CH-6900 Lugano, Switzerland.
authors.forename: Francesco
authors.initials: F
authors.lastname: Siclari
authors.affiliation: Laboratory of Molecular and Cellular Cardiology, Departments of Cardiology and Heart Surgery, Fondazione Cardiocentro Ticino, Via Tesserete 48, CH-6900 Lugano, Switzerland.
authors.forename: Tiziano
authors.initials: T
authors.lastname: Moccetti
authors.affiliation: Laboratory of Molecular and Cellular Cardiology, Departments of Cardiology and Heart Surgery, Fondazione Cardiocentro Ticino, Via Tesserete 48, CH-6900 Lugano, Switzerland Department of Cardiology, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland lucio.barile@cardiocentro.org giuseppe.vassalli@cardiocentro.org.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Vassalli
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D009203:Myocardial Infarction / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology*; D017208:Rats, Wistar; D013234:Stem Cells / Q000166:cytology*
chemical_list: D017077:Culture Media, Conditioned; D035683:MicroRNAs
keywords: Angiogenesis; Apoptosis; Cardiac progenitor cells; Cardioprotection; Exosomes; Extracellular vesicles; MicroRNA