Anaïs Kervadec1, Valérie Bellamy1, Nadia El Harane1, Lousineh Arakélian2, Valérie Vanneaux2, Isabelle Cacciapuoti2, Hany Nemetalla3, Marie-Cécile Périer1, Hadi D Toeg4, Adèle Richart1, Mathilde Lemitre1, Min Yin5, Xavier Loyer1, Jérôme Larghero6, Albert Hagège7, Marc Ruel4, Chantal M Boulanger1, Jean-Sébastien Silvestre1, Philippe Menasché8, Nisa K E Renault1. 1. INSERM U970, Hôpital Européen Georges Pompidou, Paris Centre de Recherche Cardiovasculaire, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, UMR-S970, Paris, France. 2. 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. 3. Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiology, Paris, France. 4. Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Ontario, Canada. 5. 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. 6. 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. 7. 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. 8. 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.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
BACKGROUND: 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. METHODS: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. RESULTS: 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. CONCLUSIONS: 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: Nadia El Harane; Anaïs Kervadec; Valérie Bellamy; Laetitia Pidial; Hany J Neametalla; Marie-Cécile Perier; Bruna Lima Correa; Léa Thiébault; Nicolas Cagnard; Angéline Duché; Camille Brunaud; Mathilde Lemitre; Jeanne Gauthier; Alexandra T Bourdillon; Marc P Renault; Yeranuhi Hovhannisyan; Solenne Paiva; Alexandre R Colas; Onnik Agbulut; Albert Hagège; Jean-Sébastien Silvestre; Philippe Menasché; Nisa K E Renault Journal: Eur Heart J Date: 2018-05-21 Impact factor: 29.983
Authors: Udit Agarwal; Alex George; Srishti Bhutani; Shohini Ghosh-Choudhary; Joshua T Maxwell; Milton E Brown; Yash Mehta; Manu O Platt; Yaxuan Liang; Susmita Sahoo; Michael E Davis Journal: Circ Res Date: 2016-11-21 Impact factor: 17.367