title: Long-term functional benefits of human embryonic stem cell-derived cardiac progenitors embedded into a fibrin scaffold.
abstract: BACKGROUND
  Cardiac-committed cells and biomimetic scaffolds independently improve the therapeutic efficacy of stem cells. In this study we tested the long-term effects of their combination.
  
  
  METHODS
  Eighty immune-deficient rats underwent permanent coronary artery ligation. Five to 7 weeks later, those with an echocardiographically measured ejection fraction (EF) ≤55% were re-operated on and randomly allocated to receive a cell-free fibrin patch (n = 25), a fibrin patch loaded with 700,000 human embryonic stem cells (ESC) pre-treated to promote early cardiac differentiation (SSEA-1(+) progenitors [n = 30]), or to serve as sham-operated animals (n = 25). Left ventricular function was assessed by echocardiography at baseline and every month thereafter until 4 months. Hearts were then processed for assessment of fibrosis and angiogenesis and a 5-component heart failure score was constructed by integrating the absolute change in left ventricular end-systolic volume (LVESV) between 4 months and baseline, and the quantitative polymerase chain reaction (qPCR)-based expression of natriuretic peptides A and B, myosin heavy chain 7 and periostin. All data were recorded and analyzed in a blinded manner.
  
  
  RESULTS
  The cell-treated group consistently yielded better functional outcomes than the sham-operated group (p = 0.002 for EF; p = 0.01 for LVESV). Angiogenesis in the border zone was also significantly greater in the cell-fibrin group (p = 0.006), which yielded the lowest heart failure score (p = 0.04 vs sham). Engrafted progenitors were only detected shortly after transplantation; no grafted cells were identified after 4 months. There was no teratoma identified.
  
  
  CONCLUSIONS
  A fibrin scaffold loaded with ESC-derived cardiac progenitors resulted in sustained improvement in contractility and attenuation of remodeling without sustained donor cell engraftment. A paracrine effect, possibly on innate reparative responses, is a possible mechanism for this enduring effect.
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Bellamy
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Cell Therapy Unit and Clinical Investigation Center in Biotherapies (CBT501), INSERM UMR1160, Université Sorbonne Paris Cité, Paris, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Vanneaux
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiovascular Surgery, Université Sorbonne Paris Cité, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Bel
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiology, Université Sorbonne Paris Cité, Paris, France.
authors.forename: Hany
authors.initials: H
authors.lastname: Nemetalla
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, IBPS, UMR CNRS 8256, Biological Adaptation and Ageing, Paris, France.
authors.forename: Solène
authors.initials: S
authors.lastname: Emmanuelle Boitard
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Yohan
authors.initials: Y
authors.lastname: Farouz
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, IBPS, UMR CNRS 8256, Biological Adaptation and Ageing, Paris, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Joanne
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Perier
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Robidel
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Mandet
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiology, Université Sorbonne Paris Cité, Paris, France.
authors.forename: Albert
authors.initials: A
authors.lastname: Hagège
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Pathology, Université Sorbonne Paris Cité, Paris, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Cell Therapy Unit and Clinical Investigation Center in Biotherapies (CBT501), INSERM UMR1160, Université Sorbonne Paris Cité, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Larghero
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, IBPS, UMR CNRS 8256, Biological Adaptation and Ageing, Paris, France.
authors.forename: Onnik
authors.initials: O
authors.lastname: Agbulut
authors.affiliation: INSERM U970, Hôpital Européen Georges Pompidou, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Department of Cardiovascular Surgery, Université Sorbonne Paris Cité, Paris, France. Electronic address: philippe.menasche@egp.aphp.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Menasché
mesh_terms: D043925:Angiogenesis Inducing Agents; D000818:Animals; D015815:Cell Adhesion Molecules / Q000032:analysis; D003331:Coronary Vessels; D004452:Echocardiography; D053595:Embryonic Stem Cells; D005260:Female; D005337:Fibrin; D006333:Heart Failure; D006801:Humans; D007150:Immunohistochemistry; D008026:Ligation; D008819:Mice, Nude; D009206:Myocardium / Q000166:cytology*; D018995:Myosin Heavy Chains; D045265:Natriuretic Peptides / Q000032:analysis; D016133:Polymerase Chain Reaction; D051381:Rats; D013234:Stem Cells; D013318:Stroke Volume; D054457:Tissue Scaffolds; D016277:Ventricular Function, Left
chemical_list: D043925:Angiogenesis Inducing Agents; D015815:Cell Adhesion Molecules; D045265:Natriuretic Peptides; C512836:Postn protein, rat; D005337:Fibrin; D018995:Myosin Heavy Chains
keywords: cardiac patches; cardiac progenitors; cell transplantation; embryonic stem cells; heart failure; stem cells; tissue engineering