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Fibroblasts from human postmyocardial infarction scars acquire properties of cardiomyocytes after transduction with a recombinant myocardin gene

John van Tuyn^*,,,1, Daniël A. Pijnappels^*,1, Antoine A. F. de Vries, Ingrid de Vries, Ietje van der Velde-van Dijke, Shoshan Knaän-Shanzer, Arnoud van der Laarse^*, Martin J. Schalij^* and Douwe E. Atsma^*,2

^* Department of Cardiology,

Virus and Stem Cell Biology Laboratory, Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands; and

Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands

²Correspondence: Department of Cardiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: d.e.atsma{at}lumc.nl

Myocardial scar formation impairs heart function by inducing cardiac remodeling, decreasing myocardial compliance, and compromising normal electrical conduction. Conversion of myocardial scar fibroblasts (MSFs) into (functional) cardiomyocytes may be an effective alternative treatment to limit loss of cardiac performance after myocardial injury. In this study, we investigated whether the phenotype of MSFs can be modified by gene transfer into cells with properties of cardiomyocytes. To this end, fibroblasts from postmyocardial infarction scars of human left ventricles were isolated and characterized by cell biological, immunological, and molecular biological assays. Cultured human MSFs express GATA4 and connexin 43 and display adipogenic differentiation potential. Infection of human MSFs with a lentivirus vector encoding the potent cardiogenic transcription factor myocardin renders them positive for a wide variety of cardiomyocyte-specific proteins, including sarcomeric components, transcription factors, and ion channels, and induces the expression of several smooth muscle marker genes. Forced myocardin expression also endowed human MSFs with the ability to transmit an action potential and to repair an artificially created conduction block in cardiomyocyte cultures. These finding indicate that in vivo myocardin gene transfer may potentially limit cardiomyocyte loss, myocardial fibrosis, and disturbances in electrical conduction caused by myocardial infarction.—van Tuyn, J., Pijnappels, D. A., de Vries, A. A. F., de Vries, I., van der Velde-van Dijke, I., Knaän-Shanzer, S., van der Laarse, A., Schalij, M. J., Atsma, D. E. Fibroblasts from human postmyocardial infarction scars acquire properties of cardiomyocytes after transduction with a recombinant myocardin gene.

Key Words: conduction (block) • fibrosis • gene transfer • heart infarction • myocytes

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