Non-cultured cell transplantation in an ovine model of non-ischemic heart failure.
OBJECTIVE
Cell therapy may be a promising alternative or adjunct to current treatment modalities for ischemic heart failure. But little is known on the impact of myogenic cell transplantation in large animal models of non-ischemic cardiomyopathy. The aim of the present study was to explore whether an ovine model of toxin-induced heart disease could benefit from non-cultured skeletal muscle cell transplantation.


METHODS
Sequential intracoronary injections of doxorubicin (0.75 mg/kg) were carried out every 2 weeks until echocardiographic detection of myocardial dysfunction. Sheep were then randomly assigned to either non-cultured cell transplantation (n=8) or placebo injection (n=5). For the cell therapy group, a skeletal muscle biopsy (about 10 g) was explanted from each animal approximately 3h before grafting. After thoracotomy, 20 epicardial injections were carried out. The animals were assessed one last time before sacrifice, 2 months after the thoracotomy. Cells were tracked with cmDiI (red fluorescence) and characterized with immunohistochemistry with monoclonal antibodies to a fast skeletal isoform of myosin heavy chain.


RESULTS
Two months after intramyocardial grafting, tissue Doppler imaging and conventional echocardiographic assessment of the groups showed a marked improvement in the non-cultured cell therapy group. Ejection fraction (EF) (p<0.05) as well as systolic endocardial velocities (p<0.01) improved versus the placebo group. CmDiI and skeletal myosin heavy chain expression was detected in all animals at 2 months after implantation confirming engraftment of skeletal muscle cells.


CONCLUSIONS
In conclusion, our data indicate that non-cultured muscle cell transplantation is feasible and may translate into a functional benefit in an ovine model of dilated heart failure.
Borenstein
Nicolas
N
IMM Recherche, 42 bd Jourdan, 75014 Paris, France. nicolas.borenstein@imm.fr
Chetboul
Valérie
V
Bruneval
Patrick
P
Hekmati
Mehrak
M
Tissier
Renaud
R
Behr
Luc
L
Derumeaux
Geneviève
G
Montarras
Didier
D
D000818:Animals; D001783:Blood Flow Velocity; D002470:Cell Survival; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin; D015150:Echocardiography, Doppler; D005240:Feasibility Studies; D006085:Graft Survival; D006333:Heart Failure / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000503:physiopathology / Q000628:therapy*; D018485:Muscle Fibers, Skeletal / Q000637:transplantation*; D009206:Myocardium / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism; D034561:Sheep, Domestic; D013318:Stroke Volume
D018031:Connexin 43; D004317:Doxorubicin; D018995:Myosin Heavy Chains