Human embryonic stem cell transplantation to repair the infarcted myocardium.
OBJECTIVE
To test the hypothesis that human embryonic stem cells (hESCs) can be guided to form new myocardium by transplantation into the normal or infarcted heart, and to assess the influence of hESC-derived cardiomyocytes (hESCMs) on cardiac function in a rat model of myocardial infarction (MI).


METHODS
Undifferentiated hESCs (0.5-1x10(6)), human embryoid bodies (hEBs) (4-8 days; 0.5-1x10(6)), 0.1 mm pieces of embryonic stem-derived beating myocardial tissue, and phosphate-buffered saline (control) were injected into the normal or infarcted myocardium of athymic nude rats (n = 58) by direct injection into the muscle or into preimplanted three-dimensional alginate scaffold. By 2-4 weeks after transplantation, heart sections were examined to detect the human cells and differentiation with fluorescent in situ hybridisation, using DNA probes specific for human sex chromosomes and HLA-DR or HLA-ABC immunostaining.


RESULTS
Microscopic examination showed transplanted human cells in the normal, and to a lesser extent in the infarcted myocardium (7/7 vs 2/6; p<0.05). The transplanted hESCs and hEBs rarely created new vessels and did not form new myocardium. Transplantation of hESCM tissue into normal heart produced islands of disorganised myofibres, fibrosis and, in a single case, a teratoma. However, transplantation of hESCMs into the infarcted myocardium did prevent post-MI dysfunction and scar thinning.


CONCLUSIONS
Undifferentiated hESCs and hEBs are not directed to form new myocardium after transplantation into normal or infarcted heart and may create teratoma. Nevertheless, this study shows that hESC-derived cardiomyocyte transplantation can attenuate post-MI scar thinning and left ventricular dysfunction.
Leor
Jonathan
J
Neufeld Cardiac Research Institute, Sheba Medical Centre, Tel-Aviv University, Tel-Hashomer, Israel. leorj@post.tau.ac.il
Gerecht
Sharon
S
Cohen
Smadar
S
Miller
Liron
L
Holbova
Radka
R
Ziskind
Anna
A
Shachar
Michal
M
Feinberg
Micha S
MS
Guetta
Esther
E
Itskovitz-Eldor
Joseph
J
D000818:Animals; D002460:Cell Line; D004452:Echocardiography; D053595:Embryonic Stem Cells / Q000637:transplantation*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000637:transplantation*; D051381:Rats; D011923:Rats, Nude; D033581:Stem Cell Transplantation / Q000379:methods*; D020257:Ventricular Remodeling