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1 Medicine, University of Vermont, Colchester, Vermont, United States
2 University of Wisconsin, Madison, Madison, Wisconsin, United States
3 University of Wisconsin - Madison; University of Wisconsin - Madison, United States
* To whom correspondence should be addressed. E-mail: dinender.kumar{at}uvm.edu.
We have previously shown that mouse embryonic stem (ES) cells transplanted following myocardial infarction (MI) differentiate into the major cell types in the heart and improve cardiac function. However, the extent of regeneration was relatively meager compared to the observed functional improvement. Therefore, we hypothesize that mechanisms in addition to regeneration contribute to the functional improvement from ES cell therapy. In this study, we examined the effect of mouse ES cells transplanted post-MI on cardiac apoptosis, hypertrophy and fibrosis. MI was produced by left coronary artery ligation in C57BL/6 mice. Two different mouse ES cell lines, expressing eGFP and 
-galactosidase respectively, were tested. Post-MI intramyocardial injection of 3X104 ES cells was compared to injection of medium alone. Terminal deoxynucleotidyl nick end labeling (TUNEL) staining, immunofluorescence, and histology were used to examine the effect of transplanted ES cells on apoptosis, hypertrophy and fibrosis. Two weeks post-MI, ES cell transplanted hearts exhibited a significant decrease in TUNEL stained nuclei (mean±SE; MI+medium=12±1.5%; MI±ES cells=6.6±1%, p<0.05). TUNEL positive nuclei were confirmed to be apoptotic by co-labeling with a caspase-3 antibody. Cardiac fibrosis was 57% less in the MI+ES cell group compared with MI+medium group (p<0.05) as seen with Masson’s Trichrome. Picrosirius red (PSR) staining confirmed a decreased amount of collagen present in the MI+ES cell group. Cardiomyocyte hypertrophy was significantly decreased following ES cells transplantation compared with medium control animals. In conclusion, transplanted mouse ES cells in the infarcted heart inhibit apoptosis, fibrosis and hypertrophy thereby reducing adverse remodeling.
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