Transplantation of cardiac-committed mouse embryonic stem cells to infarcted sheep myocardium: a preclinical study

• Published in: The Lancet (British edition) Vol. 366; no. 9490; pp. 1005 - 1012
• Main Authors: Ménard, Claudine, Hagège, Albert A, Agbulut, Onnik, Barro, Marietta, Morichetti, Miguel Cortes, Brasselet, Camille, Bel, Alain, Messas, Emmanuel, Bissery, Alvine, Bruneval, Patrick, Desnos, Michel, Pucéat, Michel, Menasché, Philippe
• Format: Journal Article
• Language: English
• Published: London Elsevier Ltd 17-09-2005; Lancet; Elsevier Limited
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animal models; Animals; Applied cell therapy and gene therapy; Biological and medical sciences; Cardiology. Vascular system; Cell Differentiation; Cell Division; Cell Lineage; Coronary heart disease; Embryo, Mammalian - cytology; General aspects; Graft Survival; Growth factors; Heart; Heart failure; Leukemia; Medical sciences; Mice; Myocardial infarction; Myocardial Infarction - physiopathology; Myocardial Infarction - therapy; Myocardium - cytology; Myocardium - metabolism; Rodents; Sheep; Stem Cell Transplantation; Stem cells; Stroke Volume; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplants & implants; Tumors; Heart; Myocardial infarction; Embryo; Cell therapy; Regenerative medicine; Stem cell; Rodentia; Preclinical study; Cardiovascular disease; Transplantation; Myocardial disease; Vertebrata; Mammalia; Treatment; Mouse; Heart disease; Surgery; Animal; Graft; Sheep; Circulatory system; Artiodactyla; Ungulata
• ISSN: 0140-6736; 1474-547X
• DOI: 10.1016/S0140-6736(05)67380-1

Heart failure develops after myocardial infarction and is a major cause of morbidity and mortality. The ability to direct differentiation of embryonic stem cells (ESC) towards a cardiomyogenic phenotype makes them an attractive therapeutic option for cardiac repair, but species-specific and individual-specific immunological imprinting remains a hurdle. Our aim was to ascertain whether the purported immune privilege of ESC allows for their cross-species engraftment in a clinically relevant large-animal model.
We studied engraftment and differentiation of cardiac-committed mouse ESC in 18 sheep in which a myocardial infarction had been induced; nine controls received medium and nine sheep (five of which were immunosuppressed) received ESC. The gain in myocardial function was measured by echocardiography 1 month after cell transplantation.
Cardiac-committed murine ESC engrafted in infarcted myocardium of immunosuppressed and immunocompetent sheep, and differentiated into mature cardiomyocytes that expressed connexins. Colonisation of the scar area by ESC was accompanied by a functional benefit of the damaged myocardium. Left-ventricular ejection fraction deteriorated in the control group by a median of 9·9% (range −20 to 0·3) relative to baseline (p=0·011) whereas in the treated group it improved by 6·6% (−5·7 to 50·8; comparison between groups p=0·002).
These findings obtained in a clinically relevant large-animal model of heart failure strengthen the potential therapeutic use of ESC to regenerate the severely dysfunctional myocardium and bring additional evidence for an immune privilege of these cells.