Composite Cell Sheets A Further Step Toward Safe and Effective Myocardial Regeneration by Cardiac Progenitors Derived From Embryonic Stem Cells

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. To address these issues, we developed a composite construct made of a sheet of adipose tissue-derived stroma cells and embryonic stem cell-derived cardia...

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Published in:	Circulation (New York, N.Y.) Vol. 122; no. 11; pp. S118 - S123
Main Authors:	BEL, Alain, PLANAT-BERNARD, Valérie, PEYRARD, Séverine, LARGHERO, Jérôme, POULY, Julia, BINDER, Patrice, GARCIA, Sylvie, SHIMIZU, Tatsuya, SAWA, Yoshiki, OKANO, Teruo, BRUNEVAL, Patrick, DESNOS, Michel, SAITO, Atsuhiro, HAGEGE, Albert A, CASTEILLA, Louis, PUCEAT, Michel, MENASCHE, Philippe, BONNEVIE, Lionel, BELLAMY, Valérie, SABBAH, Laurent, BELLABAS, Linda, BRINON, Benjamin, VANNEAUX, Valérie, PRADEAU, Pascal
Format:	Journal Article
Language:	English
Published:	Hagerstown, MD Lippincott Williams & Wilkins 14-09-2010
Subjects:	Adipose Tissue - cytology Adipose Tissue - transplantation Animals Biological and medical sciences Blood and lymphatic vessels Blood vessels and receptors Cardiology. Vascular system Cell Differentiation Disease Models, Animal Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous Embryonic Stem Cells - transplantation Fundamental and applied biological sciences. Psychology Humans Lewis X Antigen Macaca mulatta Medical sciences Mice Myocardial Infarction - therapy Myocardium - pathology Myocytes, Cardiac - cytology Myocytes, Cardiac - metabolism Neovascularization, Physiologic Regeneration Stem Cell Transplantation - methods Stromal Cells Transplantation, Autologous Transplantation, Homologous Vertebrates: cardiovascular system Myocardial infarction Heart failure Regeneration stem cells cells Stem cell transplantation Cardiovascular disease Coronary heart disease Myocardial disease Progenitor cell
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Summary:	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. 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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0009-7322 1524-4539
DOI:	10.1161/CIRCULATIONAHA.109.927293