Composite cell sheets: a further step toward safe and effective myocardial regeneration by cardiac progenitors derived from embryonic stem cells.
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.
Bel
Alain
A
Assistance Publique-Hôpitaux de Paris, Department of Cardiovascular Surgery, Hôpital Européen Georges Pompidou, University Paris Descartes, INSERM U633, Paris, France.
Planat-Bernard
Valérie
V
Saito
Atsuhiro
A
Bonnevie
Lionel
L
Bellamy
Valérie
V
Sabbah
Laurent
L
Bellabas
Linda
L
Brinon
Benjamin
B
Vanneaux
Valérie
V
Pradeau
Pascal
P
Peyrard
Séverine
S
Larghero
Jérôme
J
Pouly
Julia
J
Binder
Patrice
P
Garcia
Sylvie
S
Shimizu
Tatsuya
T
Sawa
Yoshiki
Y
Okano
Teruo
T
Bruneval
Patrick
P
Desnos
Michel
M
Hagège
Albert A
AA
Casteilla
Louis
L
Pucéat
Michel
M
Menasché
Philippe
P
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
D016256:Lewis X Antigen