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


RESULTS
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).


CONCLUSIONS
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.
Ménard
Claudine
C
Centre National de la Recherche Scientifique, FRE2593, Centre de Recherche de Biochimie Macromoléculaire, Montpellier, France.
Hagège
Albert A
AA
Agbulut
Onnik
O
Barro
Marietta
M
Morichetti
Miguel Cortes
MC
Brasselet
Camille
C
Bel
Alain
A
Messas
Emmanuel
E
Bissery
Alvine
A
Bruneval
Patrick
P
Desnos
Michel
M
Pucéat
Michel
M
Menasché
Philippe
P
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D019070:Cell Lineage; D004622:Embryo, Mammalian / Q000166:cytology*; D006085:Graft Survival; D051379:Mice; D009203:Myocardial Infarction / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000166:cytology* / Q000378:metabolism; D012756:Sheep; D033581:Stem Cell Transplantation; D013318:Stroke Volume