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Transplanted embryonic stem cells following mouse myocardial infarction inhibit apoptosis and cardiac remodeling

¹Department of Medicine, College of Medicine, University of Vermont, Colchester, Vermont; ²Department of Anatomy, ³Department of Medicine, and ⁴WiCell Research Institute, University of Wisconsin, Madison, Wisconsin

Submitted 21 November 2006 ; accepted in final form 2 April 2007

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 with 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, fibrosis, and hypertrophy. MI was produced by left coronary artery ligation in C57BL/6 mice. Two different mouse ES cell lines, expressing enhanced green fluorescent protein and -galactosidase, respectively, were tested. Post-MI intramyocardial injection of 3 x 10⁴ ES cells was compared with injection of medium alone. Terminal deoxynucleotidyl nick end labeling (TUNEL), immunofluorescence, and histology were used to examine the effect of transplanted ES cells on apoptosis, fibrosis, and hypertrophy. 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 colabeling with a caspase-3 antibody. Cardiac fibrosis was 57% less in the MI+ES cell group compared with the MI + medium group (P < 0.05) as shown with Masson's trichrome staining. Picrosirius red staining confirmed a decreased amount of collagen present in the MI+ES cell group. Cardiomyocyte hypertrophy was significantly decreased following ES cell 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.

cardiomyocytes; cell therapy; fibrosis; TIMP-1

This article has been cited by other articles:

				D. K. Singla, R. D. Singla, and D. E. McDonald Factors released from embryonic stem cells inhibit apoptosis in H9c2 cells through PI3K/Akt but not ERK pathway Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H907 - H913. [Abstract] [Full Text] [PDF]

				C. Lygate Letter to the editor: Infarct size measurements are critically important when comparing interventions affecting ventricular remodeling Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3221 - H3221. [Full Text] [PDF]

				D. K. Singla, G. E. Lyon, and T. J. Kamp Reply to "Letter to the editor: Infarct size measurements are critically important when comparing interventions affecting ventricular remodeling" Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3222 - H3222. [Full Text] [PDF]