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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

Departments of ^aCardiology,
^bMolecular Cell Biology,
^cAnatomy and Embryology and
^dDivision of Image Processing, Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands

Key Words. Mesenchymal stem cells • Cellular therapy • Transgene expression • NOD/scid mouse

Correspondence: M.J. Schalij, Ph.D., M.D., Department of Cardiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Telephone: 31-71-526-2020; Fax: 31-71-526-6809; e-mail: M.J.Schalij{at}lumc.nl

Received July 9, 2007; accepted for publication January 9, 2008.
First published online in STEM CELLS EXPRESS   January 17, 2008.



Human mesenchymal stem cells (hMSCs) have only a limited differentiation potential toward cardiomyocytes. Forced expression of the cardiomyogenic transcription factor myocardin may stimulate hMSCs to acquire a cardiomyogenic phenotype, thereby improving their possible therapeutic potential. hMSCs were transduced with green fluorescent protein (GFP) and myocardin (hMSC_myoc) or GFP and empty vector (hMSC). After coronary ligation in immune-compromised NOD/scid mice, hMSC_myoc (n = 10), hMSC (n = 10), or medium only (n = 12) was injected into the infarct area. Sham-operated mice (n = 12) were used to determine baseline characteristics. Left ventricular (LV) volumes and ejection fraction (EF) were serially (days 2 and 14) assessed using 9.4-T magnetic resonance imaging. LV pressure-volume measurements were performed at day 15, followed by histological evaluation. At day 2, no differences in infarct size, LV volumes, or EF were observed among the myocardial infarction groups. At day 14, left ventricular ejection fraction in both cell-treated groups was preserved compared with the nontreated group; in addition, hMSC_myoc injection also reduced LV volumes compared with medium injection (p < .05). Furthermore, pressure-volume measurements revealed a significantly better LV function after hMSC_myoc injection compared with hMSC treatment. Immunohistochemistry at day 15 demonstrated that the engraftment rate was higher in the hMSC_myoc group compared with the hMSC group (p < .05). Furthermore, these cells expressed a number of cardiomyocyte-specific markers not observed in the hMSC group. After myocardial infarction, injection of hMSC_myoc 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.

Disclosure of potential conflicts of interest is found at the end of this article.

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