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EMBRYONIC STEM CELLS

Generation and Characterization of Functional Cardiomyocytes from Rhesus Monkey Embryonic Stem Cells

^a Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO) and Department of Thoracic and Cardiovascular Surgery, Hannover Medical School, Hannover, Germany;
^b Institute of Neurophysiology, University of Cologne, Cologne, Germany;
^c Department of Cell Biology; Hannover Medical School, Hannover, Germany;
^d Department of Obstetrics and Gynecology, Rambam Medical Center, Faculty of Medicine, The Technion, Haifa, Israel

Key Words. Embryonic stem cells • Differentiation • Cardiomyocytes • Primates

Correspondence: Ulrich Martin, Ph.D., Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Podbielskistr. 380, 30659 Hannover, Germany. Telephone: +49 (511) 532-8820; Fax: +49 (511) 532-8819; e-mail: martin.ulrich{at}mh-hannover.de

Received August 9, 2005; accepted for publication March 6, 2006.

Embryonic stem cells (ESCs) from mice and humans (hESCs) have been shown to be able to efficiently differentiate toward cardiomyocytes (CMs). Because murine ESCs and hESCs do not allow for establishment of pre-clinical allogeneic transplantation models, the aim of our study was to generate functional CMs from rhesus monkey ESCs (rESCs). Although formation of ectodermal and neuronal/glial cells appears to be the default pathway of the rESC line R366.4, we were able to change this commitment and to direct generation of endodermal/mesodermal cells and further differentiation toward CMs. Differentiation of rESCs resulted in an average of 18% of spontaneously contracting embryoid bodies (EBs) from rESCs. Semiquantitative reverse transcription-polymerase chain reaction analyses demonstrated expression of marker genes typical for endoderm, mesoderm, cardiac mesoderm, and CMs, including brachyury, goosecoid, Tbx-5, Tbx-20, Mesp1, Nkx2.5, GATA-4, FOG-2, Mlc2a, MLC2v, ANF, and -MHC in rESC-derived CMs. Immunohistological and ultrastructural studies showed expression of CM-typical proteins, including sarcomeric actinin, troponin T, titin, connexin 43, and cross-striated muscle fibrils. Electrophysiological studies by means of multielectrode arrays revealed evidence of functionality, electrical coupling, and ß-adrenergic signaling of the generated CMs. This is the first study demonstrating generation of functional CMs derived from rESCs. In contrast to hESCs, rESCs allow for establishment of pre-clinical allogeneic transplantation models. Moreover, rESC-derived CMs represent a cell source for the development of high-throughput assays for cardiac safety pharmacology.

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