title: Cardiovascular progenitor-derived extracellular vesicles recapitulate the beneficial effects of their parent cells in the treatment of chronic heart failure.
abstract: 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 included in the study were treated with hESC-Pg, EV, or Minimal Essential Medium Alpha Medium (alpha-MEM; vehicle control) delivered by percutaneous injections under echocardiographic guidance into the peri-infarct myocardium. functional and histologic end-points were blindly assessed 6 weeks later, and hearts were processed for gene profiling. Genes differentially expressed between control hearts and hESC-Pg-treated and EV-treated hearts were clustered into functionally relevant pathways.
  
  
  
  At 6 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 with baseline values despite the absence of any transplanted hESC-Pg or human embryonic stem cell-derived cardiomyocytes in the treated mouse hearts. Equal benefits were seen with the injection of hESC-Pg-derived EV, whereas animals injected with alpha-MEM (vehicle control) did not improve significantly. Histologic examination suggested a slight reduction in infarct size in hESC-Pg-treated animals and EV-treated animals compared with alpha-MEM-treated control animals. In the hESC-Pg-treated and EV-treated groups, heart gene profiling identified 927 genes that were similarly upregulated compared with the control group. 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 and/or proliferation or DNA repair as well as pathways related to decreased fibrosis and heart failure.
  
  
  
  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. Although 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.
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris Centre de Recherche Cardiovasculaire, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S970, Paris, France.
authors.forename: Anaïs
authors.initials: A
authors.lastname: Kervadec
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris Centre de Recherche Cardiovasculaire, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S970, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Bellamy
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris Centre de Recherche Cardiovasculaire, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S970, Paris, France.
authors.forename: Nadia
authors.initials: N
authors.lastname: El Harane
authors.affiliation: Cell Therapy Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris, France; INSERM, CIC de Biothérapies (CBT-501) and U1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.
authors.forename: Lousineh
authors.initials: L
authors.lastname: Arakélian
authors.affiliation: Cell Therapy Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris, France; INSERM, CIC de Biothérapies (CBT-501) and U1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Vanneaux
authors.affiliation: Cell Therapy Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris, France; INSERM, CIC de Biothérapies (CBT-501) and U1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cacciapuoti
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiology, Paris, France.
authors.forename: Hany
authors.initials: H
authors.lastname: Nemetalla
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris Centre de Recherche Cardiovasculaire, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S970, Paris, France.
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Périer
authors.affiliation: Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Hadi D
authors.initials: HD
authors.lastname: Toeg
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris Centre de Recherche Cardiovasculaire, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S970, Paris, France.
authors.forename: Adèle
authors.initials: A
authors.lastname: Richart
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris Centre de Recherche Cardiovasculaire, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S970, Paris, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Lemitre
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris Centre de Recherche Cardiovasculaire, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S970, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Min
authors.initials: M
authors.lastname: Yin
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris Centre de Recherche Cardiovasculaire, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S970, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Loyer
authors.affiliation: Cell Therapy Unit, Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Paris, France; INSERM, CIC de Biothérapies (CBT-501) and U1160, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France; University Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Larghero
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris Centre de Recherche Cardiovasculaire, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S970, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiology, Paris, France.
authors.forename: Albert
authors.initials: A
authors.lastname: Hagège
authors.affiliation: Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Ruel
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris Centre de Recherche Cardiovasculaire, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S970, Paris, France.
authors.forename: Chantal M
authors.initials: CM
authors.lastname: Boulanger
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris Centre de Recherche Cardiovasculaire, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S970, Paris, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Silvestre
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris Centre de Recherche Cardiovasculaire, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S970, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiovascular Surgery, Paris, France. Electronic address: philippe.menasche@aphp.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Menasché
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris Centre de Recherche Cardiovasculaire, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S970, Paris, France.
authors.forename: Nisa K E
authors.initials: NK
authors.lastname: Renault
mesh_terms: D000818:Animals; D002908:Chronic Disease; D053595:Embryonic Stem Cells; D000067128:Extracellular Vesicles; D006333:Heart Failure; D006801:Humans; D051379:Mice; D009203:Myocardial Infarction; D009206:Myocardium; D032383:Myocytes, Cardiac
keywords: cardiovascular progenitor cells; cell therapy; embryonic stem cells; exosomes; extracellular vesicles; heart failure; microparticles