title: Composite cell sheets: a further step toward safe and effective myocardial regeneration by cardiac progenitors derived from embryonic stem cells.
abstract: BACKGROUND
  The safety and efficacy of myocardial regeneration using embryonic stem cells are limited by the risk of teratoma and the high rate of cell death.
  
  
  RESULTS
  To address these issues, we developed a composite construct made of a sheet of adipose tissue-derived stroma cells and embryonic stem cell-derived cardiac progenitors. Ten Rhesus monkeys underwent a transient coronary artery occlusion followed, 2 weeks later, by the open-chest delivery of the composite cell sheet over the infarcted area or a sham operation. The sheet was made of adipose tissue-derived stroma cells grown from a biopsy of autologous adipose tissue and cultured onto temperature-responsive dishes. Allogeneic Rhesus embryonic stem cells were committed to a cardiac lineage and immunomagnetically sorted to yield SSEA-1(+) cardiac progenitors, which were then deposited onto the cell sheet. Cyclosporine was given for 2 months until the animals were euthanized. Preimplantation studies showed that the SSEA-1(+) progenitors expressed cardiac markers and had lost pluripotency. After 2 months, there was no teratoma in any of the 5 cell-treated monkeys. Analysis of >1500 histological sections showed that the SSEA-1(+) cardiac progenitors had differentiated into cardiomyocytes, as evidenced by immunofluorescence and real-time polymerase chain reaction. There were also a robust engraftment of autologous adipose tissue-derived stroma cells and increased angiogenesis compared with the sham animals.
  
  
  CONCLUSIONS
  These data collected in a clinically relevant nonhuman primate model show that developmentally restricted SSEA-1(+) cardiac progenitors appear to be safe and highlight the benefit of the epicardial delivery of a construct harboring cells with a cardiomyogenic differentiation potential and cells providing them the necessary trophic support.
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Department of Cardiovascular Surgery, Hôpital Européen Georges Pompidou, University Paris Descartes, INSERM U633, Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Bel
authors.forename: Valérie
authors.initials: V
authors.lastname: Planat-Bernard
authors.forename: Atsuhiro
authors.initials: A
authors.lastname: Saito
authors.forename: Lionel
authors.initials: L
authors.lastname: Bonnevie
authors.forename: Valérie
authors.initials: V
authors.lastname: Bellamy
authors.forename: Laurent
authors.initials: L
authors.lastname: Sabbah
authors.forename: Linda
authors.initials: L
authors.lastname: Bellabas
authors.forename: Benjamin
authors.initials: B
authors.lastname: Brinon
authors.forename: Valérie
authors.initials: V
authors.lastname: Vanneaux
authors.forename: Pascal
authors.initials: P
authors.lastname: Pradeau
authors.forename: Séverine
authors.initials: S
authors.lastname: Peyrard
authors.forename: Jérôme
authors.initials: J
authors.lastname: Larghero
authors.forename: Julia
authors.initials: J
authors.lastname: Pouly
authors.forename: Patrice
authors.initials: P
authors.lastname: Binder
authors.forename: Sylvie
authors.initials: S
authors.lastname: Garcia
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Shimizu
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Sawa
authors.forename: Teruo
authors.initials: T
authors.lastname: Okano
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.forename: Michel
authors.initials: M
authors.lastname: Desnos
authors.forename: Albert A
authors.initials: AA
authors.lastname: Hagège
authors.forename: Louis
authors.initials: L
authors.lastname: Casteilla
authors.forename: Michel
authors.initials: M
authors.lastname: Pucéat
authors.forename: Philippe
authors.initials: P
authors.lastname: Menasché
mesh_terms: D000273:Adipose Tissue / Q000166:cytology* / Q000637:transplantation; D000818:Animals; D002454:Cell Differentiation; D004195:Disease Models, Animal; D053595:Embryonic Stem Cells / Q000637:transplantation*; D006801:Humans; D016256:Lewis X Antigen; D008253:Macaca mulatta; D051379:Mice; D009203:Myocardial Infarction / Q000628:therapy*; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D018919:Neovascularization, Physiologic; D012038:Regeneration; D033581:Stem Cell Transplantation / Q000379:methods*; D017154:Stromal Cells; D014182:Transplantation, Autologous; D014184:Transplantation, Homologous
chemical_list: D016256:Lewis X Antigen