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Stem Cell Engineering pp 119–141Cite as

Enhanced Cardiac Differentiation of Mouse Embryonic Stem Cells by Electrical Stimulation

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Abstract

Cardiovascular diseases account for more deaths than any other illness. Cardiac tissue engineering has turned to embryonic stem cells as a renewable source of myocytes for use in tissue replacement. Existing methods for stem cell differentiation toward the cardiac lineage are relatively non-specific, yielding low numbers of myocytes with varying contraction frequencies and strengths. Here we describe novel experimental approaches, utilizing an electrical stimulation regimen, aimed at increasing the efficiency of cardiac differentiation from mouse embryonic stem (mES) cells. These methods generate cardiac myocytes with functional characteristics that more closely resemble native tissues. The amplitude, duration, and frequency of the electrical stimulus as well as the timing of its onset are some of the critical experimental parameters that determine the enhancement of cardiac differentiation.

In order to form embryoid bodies, an optimum differentiation regime was followed incorporating the hanging drop method followed by suspension culture and subsequent post-plating on conductive slides with electrical stimulation. Approximately three times more stimulated mES cells exhibited evidence of cardiac differentiation than their non-stimulated counterparts, as determined by the expression of ventricular marker myosin light chain-2v. Spontaneous contractions of the stimulated cell populations began up to 1 day earlier and had an average beat frequency close to that of the stimulus applied during differentiation. The spontaneously contracting regions had larger areas of contraction, which beat more rhythmically, as determined by real-time digital imaging analysis.

Our results suggest that appropriate electrical stimulation generates greater numbers of more robust cardiac myocytes, which in turn may be better suited for repairing or regenerating an ailing heart and for use as 3D model systems for drug discovery.

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Acknowledgments

This work was supported, in part, by a Synergy Grant from Drexel University (JYK, YW, and PIL), grants from the Nanotechnology Institute of Southeastern Pennsylvania (YW and PIL), NIH (No. DE09848 to YW), and a NASA Graduate Student Research Fellowship (NAG9-138 to PRB). We are indebted to Dr. J. Hescheler for the generous gift of the MLC-2v expressing mES cell line. We thank Gregory Botta and Diane Keene for careful reading of the manuscript and for their constructive criticisms. We gratefully acknowledge the contributions of the late Professor Alan G. MacDiarmid of University of Pennsylvania (2000 Nobel laureate in Chemistry), his enthusiastic support, and numerous discussions of this project, before he passed away on February 7, 2007.

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Authors and Affiliations

  1. School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA, USA

    Paul R. Bidez III

  2. Merck Research Laboratories, Merck & Co., North Wales, PA, USA

    Paul R. Bidez III

  3. Department of Cardiothoracic Surgery, Drexel University College of Medicine, Philadelphia, PA, USA

    J. Yasha Kresh

  4. Department of Chemistry, Drexel University, Philadelphia, PA, USA

    Yen Wei

  5. Laboratory of Cellular Tissue Engineering, School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, PA, USA

    Peter I. Lelkes

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  1. Paul R. Bidez III
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Correspondence to Peter I. Lelkes .

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  1. FH Aachen, Standort Jülich, Ginsterweg 1, Jülich, 52428, Germany

    Gerhard M. Artmann

  2. Wolfson Centre for Age-Related Diseases, GKT School of Biomedical Sciences, King's College London, London, SE11UL, United Kingdom

    Stephen Minger

  3. Inst. Neurophysiologie, Universitätsklinikum Köln, Robert-Koch-Str. 39, Köln, 50931, Germany

    Jürgen Hescheler

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Bidez, P.R., Kresh, J.Y., Wei, Y., Lelkes, P.I. (2011). Enhanced Cardiac Differentiation of Mouse Embryonic Stem Cells by Electrical Stimulation. In: Artmann, G., Minger, S., Hescheler, J. (eds) Stem Cell Engineering. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-11865-4_5

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