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

Abstract

BACKGROUND:

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.

METHODS:

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.

FINDINGS:

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).

INTERPRETATION:

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.

• Authors: Claudine Ménard, Albert A Hagège, Onnik Agbulut, Marietta Barro, Miguel Cortes Morichetti, Camille Brasselet, Alain Bel, Emmanuel Messas, Alvine Bissery, Patrick Bruneval, Michel Desnos, Michel Pucéat, Philippe Menasché
• Journal: Lancet (London, England) (Lancet) 2005 Sep 17-23 Vol. 366 Issue 9490 Pg. 1005-12 ISSN: 1474-547X [Electronic] England
• PMID: 16168783 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Topics

• Animals
• Cell Differentiation
• Cell Division
• Cell Lineage
• Embryo, Mammalian (cytology)
• Graft Survival
• Mice
• Myocardial Infarction (physiopathology, therapy)
• Myocardium (cytology, metabolism)
• Sheep
• Stem Cell Transplantation
• Stroke Volume