Cardiovascular Progenitor-Derived Extracellular Vesicles Recapitulate the Beneficial Effects of their Parent Cells in the Treatment of Chronic Heart Failure

Anaïs Kervadec, Valérie Bellamy, Nadia El Harane, Lousineh Arakélian, Valérie Vanneaux, Isabelle Cacciapuoti, Hany Nemetalla, Marie-Cécile Périer, Hadi D Toeg, Adèle Richart, Mathilde Lemitre, Min Yin, Xavier Loyer, Jérôme Larghero, Albert Hagège, Marc Ruel, Chantal M. Boulanger, Jean-Sébastien Silvestre, Philippe Menasché, Nisa KE RenaultThe journal of Heart and Lung Transplantation. January 19, 2016

Cell-based therapies are being explored as a therapeutic option for patients with chronic heart failure following myocardial infarction. Extracellular vesicles (EV), including exosomes and microparticles, secreted by transplanted cells may orchestrate their paracrine therapeutic effects. We assessed whether post-infarction administration of EV released by human embryonic stem cell-derived cardiovascular progenitors (hESC-Pg) can provide equivalent benefits to administered hESC-Pg, and whether hESC-Pg and EV treatments activate similar endogenous pathways.

Mice underwent surgical occlusion of their left coronary arteries. After 2-3 weeks, 95 mice were included in the study and were treated with hESC-Pg, EV or alpha-MEM (vehicle control) delivered by percutaneous injections under echocardiographic guidance into the peri-infarct myocardium. Six weeks later, functional and histological end points were blindly assessed and hearts were processed for gene profiling. Genes differentially expressed between controls and hESC-Pg- and EV-treated hearts were then clustered into functionally relevant pathways.

Six weeks after hESC-Pg-administration, treated mice had significantly reduced left ventricular end systolic (-4.20 ± 0.96 μL or -7.5%; p=0.0007) and end-diastolic (-4.48 ± 1.47 μL or -4.4%, p=0.009) volumes compared to their baseline values despite the absence of any transplanted hESC-Pg, or hESC-derived cardiomyocytes in the treated mouse hearts. These benefits were equaled by the injection of hESC-Pg-derived EV, whereas alpha-MEM (vehicle control)-injected animals did not improve significantly. Histological examination suggested a slight reduction in infarct size in hESC-Pg- and EV-treated animals as compared to alpha-MEM controls. In both hESC-Pg- and EV-treated groups, heart gene profiling identified 927 genes that were similarly upregulated as compared to controls. Among the 49 enriched pathways associated with these up-regulated genes that could be related to cardiac function or regeneration, 78% were predicted to improve cardiac function through increased cell survival/proliferation or DNA repair, as well as decreased fibrosis and heart failure related pathways.

In this post-infarct heart failure model, either hESC-Pg or their secreted EV enhance recovery of cardiac function and similarly affect cardiac gene expression patterns that could be related to this recovery. While the mechanisms by which EV improve cardiac function remain to be determined, these results support the idea that a paracrine mechanism is sufficient to effect functional recovery in cell-based therapies for post-infarction-related chronic heart failure.
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