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First published online January 17, 2008
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2007-0523v1
26/4/1083    most recent
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Submitted on July 9, 2007
Accepted on January 9, 2008

TRANSLATIONAL AND CLINICAL RESEARCH: MESENCHYMAL STEM CELLS SERIES

Forced Myocardin Expression Enhances the Therapeutic Effect of Human Mesenchymal Stem Cells After Transplantation in Ischemic Mouse Hearts

Robert W. Grauss 1, John van Tuyn 2, Paul Steendijk 1, Elizabeth M. Winter 3, Daniël A. Pijnappels 1, Bianca Hogers 3, Adriana C. Gittenberger-De Groot 3, Rob van der Geest 4, Amoud van der Laarse 1, Antoine A. F. de Vries 5, Martin J. Schalij 1*, Douwe E. Atsma 1

1 Department of Cardiology, The Netherlands
2 Department of Cardiology, Department of Molecular Cell Biology, The Netherlands
3 Department of Anatomy and Embryology, The Netherlands
4 Division of Image Processing, Department of Radiology, Leiden University Medical Center, Leiden. The Netherlands
5 Department of Molecular Cell Biology, The Netherlands

* To whom correspondence should be addressed. E-mail: M.J.Schalij{at}lumc.nl.


  Abstract

Background: Human mesenchymal stem cells (hMSCs) only have a limited differentiation potential towards cardiomyocytes. Forced expression of the cardiomyogenic transcription factor Myocardin may stimulate hMSCs to acquire a cardiomyogenic phenotype thereby improving their possible therapeutic potential.

Methods: hMSCs were transduced with green fluorescent protein (GFP) and Myocardin (hMSCmyoc) or GFP and empty vector (hMSC). After coronary ligation in immune-compromised NOD/scid mice, hMSCmyoc (n=10), hMSC (n=10) or Medium only (n=12) were injected into the infarct area. Sham operated mice (n=12) were used to determine baseline characteristics. LV volumes and ejection fraction (EF) were serially (days 2 and 14) assessed using 9.4T MR imaging. LV pressure-volume measurements were performed at day 15 followed by histological evaluation.

Results: At day 2, no differences in infarct size, LV volumes and EF were observed between the MI groups. At day 14, LVEF in both cell-treated groups was preserved compared to the non-treated group; in addition hMSCmyoc injection also reduced LV volumes as compared to Medium injection (P<0.05). Furthermore, pressure-volume measurements revealed a significantly better LV function after hMSCmyoc injection as compared to hMSC treatment. Immunohistochemistry at day 15 demonstrated that the engraftment rate was higher in the hMSCmyoc group compared to the hMSC group (p<0.05). Furthermore, these cells expressed a number of cardiomyocyte specific markers not observed in the hMSCgroup.

Conclusions: After myocardial infarction, injection of hMSCmyoc improved LV function and limited LV remodeling, effects not observed after injection of hMSC. Furthermore, forced Myocardin expression improved engraftment, and induced a cardiomyocyte-like phenotype hMSC differentiation.

 Key Words. mesenchymal stem cells, cellular therapy, transgene expression, NOD/scid mouse




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