Nadia El Harane1,2, Anaïs Kervadec1,2, Valérie Bellamy1,2, Laetitia Pidial1,2, Hany J Neametalla3, Marie-Cécile Perier1,2, Bruna Lima Correa1,2, Léa Thiébault1,2, Nicolas Cagnard4, Angéline Duché5,6, Camille Brunaud2, Mathilde Lemitre1,2, Jeanne Gauthier1,2,7, Alexandra T Bourdillon8, Marc P Renault9, Yeranuhi Hovhannisyan10, Solenne Paiva10, Alexandre R Colas11, Onnik Agbulut10, Albert Hagège1,2,3, Jean-Sébastien Silvestre1,2, Philippe Menasché1,2,12, Nisa K E Renault1,2. 1. Institut National de la Santé et de la Recherche Médicale (INSERM), UMRS-970, Paris Centre de Recherche Cardiovasculaire, 56, rue Leblanc, 75015 Paris, France. 2. Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 3. Department of Cardiology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, 20, rue Leblanc, 75015 Paris, France. 4. Université Paris Descartes, US 024 SFR Necker, 24 Boulevard du Montparnasse, 75015 Paris, France. 5. Institut National de la Santé et de la Recherche Médicale (INSERM), U 1016, Institut Cochin, Université Paris Descartes, Sorbonne Paris Cité, 22 rue Mechain, 75014 Paris, France. 6. CNRS, Université Paris Descartes, UMR-8104, Paris, France. 7. Ecole normale supérieure, PSL Research University Paris, 45 rue d'Ulm, 75005 Paris, France. 8. Department of Engineering, Stanford University, 475 Via Ortega, Stanford, 94305 CA, USA. 9. IRIF, Université Paris Diderot-Paris 7, UMR 8243, Bâtiment Sophie Germain, 8 place Aurélie Nemours, 75013 Paris, France. 10. Sorbonne Universités, UPMC Université de Paris-6, Institut de Biologie Paris-Seine (IBPS), UMR CNRS 8256, Biological Adaptation and Ageing, 4 Place Jussieu, 75005 Paris, France. 11. Sanford Burnham Prebys Medical Discovery Institute, Development, Aging and Regeneration Program, 10901 N Torrey Pines Rd, La Jolla, 92037 CA, USA. 12. Department of Cardiovascular Surgery, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, 20, rue Leblanc, 75015 Paris, France.
Abstract
Aims: We have shown that extracellular vesicles (EVs) secreted by embryonic stem cell-derived cardiovascular progenitor cells (Pg) recapitulate the therapeutic effects of their parent cells in a mouse model of chronic heart failure (CHF). Our objectives are to investigate whether EV released by more readily available cell sources are therapeutic, whether their effectiveness is influenced by the differentiation state of the secreting cell, and through which mechanisms they act. Methods and results: The total EV secreted by human induced pluripotent stem cell-derived cardiovascular progenitors (iPSC-Pg) and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) were isolated by ultracentrifugation and characterized by Nanoparticle Tracking Analysis, western blot, and cryo-electron microscopy. In vitro bioactivity assays were used to evaluate their cellular effects. Cell and EV microRNA (miRNA) content were assessed by miRNA array. Myocardial infarction was induced in 199 nude mice. Three weeks later, mice with left ventricular ejection fraction (LVEF) ≤ 45% received transcutaneous echo-guided injections of iPSC-CM (1.4 × 106, n = 19), iPSC-Pg (1.4 × 106, n = 17), total EV secreted by 1.4 × 106 iPSC-Pg (n = 19), or phosphate-buffered saline (control, n = 17) into the peri-infarct myocardium. Seven weeks later, hearts were evaluated by echocardiography, histology, and gene expression profiling, blinded to treatment group. In vitro, EV were internalized by target cells, increased cell survival, cell proliferation, and endothelial cell migration in a dose-dependent manner and stimulated tube formation. Extracellular vesicles were rich in miRNAs and most of the 16 highly abundant, evolutionarily conserved miRNAs are associated with tissue-repair pathways. In vivo, EV outperformed cell injections, significantly improving cardiac function through decreased left ventricular volumes (left ventricular end systolic volume: -11%, P < 0.001; left ventricular end diastolic volume: -4%, P = 0.002), and increased LVEF (+14%, P < 0.0001) relative to baseline values. Gene profiling revealed that EV-treated hearts were enriched for tissue reparative pathways. Conclusion: Extracellular vesicles secreted by iPSC-Pg are effective in the treatment of CHF, possibly, in part, through their specific miRNA signature and the associated stimulation of distinct cardioprotective pathways. The processing and regulatory advantages of EV could make them effective substitutes for cell transplantation.
Aims: We have shown that extracellular vesicles (EVs) secreted by embryonic stem cell-derived cardiovascular progenitor cells (Pg) recapitulate the therapeutic effects of their parent cells in a mouse model of chronic heart failure (CHF). Our objectives are to investigate whether EV released by more readily available cell sources are therapeutic, whether their effectiveness is influenced by the differentiation state of the secreting cell, and through which mechanisms they act. Methods and results: The total EV secreted by human induced pluripotent stem cell-derived cardiovascular progenitors (iPSC-Pg) and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) were isolated by ultracentrifugation and characterized by Nanoparticle Tracking Analysis, western blot, and cryo-electron microscopy. In vitro bioactivity assays were used to evaluate their cellular effects. Cell and EV microRNA (miRNA) content were assessed by miRNA array. Myocardial infarction was induced in 199 nude mice. Three weeks later, mice with left ventricular ejection fraction (LVEF) ≤ 45% received transcutaneous echo-guided injections of iPSC-CM (1.4 × 106, n = 19), iPSC-Pg (1.4 × 106, n = 17), total EV secreted by 1.4 × 106 iPSC-Pg (n = 19), or phosphate-buffered saline (control, n = 17) into the peri-infarct myocardium. Seven weeks later, hearts were evaluated by echocardiography, histology, and gene expression profiling, blinded to treatment group. In vitro, EV were internalized by target cells, increased cell survival, cell proliferation, and endothelial cell migration in a dose-dependent manner and stimulated tube formation. Extracellular vesicles were rich in miRNAs and most of the 16 highly abundant, evolutionarily conserved miRNAs are associated with tissue-repair pathways. In vivo, EV outperformed cell injections, significantly improving cardiac function through decreased left ventricular volumes (left ventricular end systolic volume: -11%, P < 0.001; left ventricular end diastolic volume: -4%, P = 0.002), and increased LVEF (+14%, P < 0.0001) relative to baseline values. Gene profiling revealed that EV-treated hearts were enriched for tissue reparative pathways. Conclusion: Extracellular vesicles secreted by iPSC-Pg are effective in the treatment of CHF, possibly, in part, through their specific miRNA signature and the associated stimulation of distinct cardioprotective pathways. The processing and regulatory advantages of EV could make them effective substitutes for cell transplantation.
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