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

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 individu...

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Published in:The Lancet (British edition) 2005-09, Vol.366 (9490), p.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
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Language:English
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Summary: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.
ISSN:0140-6736
1474-547X
DOI:10.1016/S0140-6736(05)67380-1