title: 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.
  
  
  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.
authors.affiliation: Centre National de la Recherche Scientifique, FRE2593, Centre de Recherche de Biochimie Macromoléculaire, Montpellier, France.
authors.forename: Claudine
authors.initials: C
authors.lastname: Ménard
authors.forename: Albert A
authors.initials: AA
authors.lastname: Hagège
authors.forename: Onnik
authors.initials: O
authors.lastname: Agbulut
authors.forename: Marietta
authors.initials: M
authors.lastname: Barro
authors.forename: Miguel Cortes
authors.initials: MC
authors.lastname: Morichetti
authors.forename: Camille
authors.initials: C
authors.lastname: Brasselet
authors.forename: Alain
authors.initials: A
authors.lastname: Bel
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Messas
authors.forename: Alvine
authors.initials: A
authors.lastname: Bissery
authors.forename: Patrick
authors.initials: P
authors.lastname: Bruneval
authors.forename: Michel
authors.initials: M
authors.lastname: Desnos
authors.forename: Michel
authors.initials: M
authors.lastname: Pucéat
authors.forename: Philippe
authors.initials: P
authors.lastname: Menasché
mesh_terms: 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