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Embryonic Stem Cells |
1 Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO) and Department of Thoracic and Cardiovascular Surgery, Hannover Medical School, Hannover, Germany
2 Institute of Neurophysiology, University of Cologne, Cologne, Germany
3 Department of Cell Biology, Hannover Medical School, Hannover, Germany
4 Department of Obstetrics and Gynecology, Rambam Medical Center, Faculty of Medicine, The Technion, Haifa, Israel
* To whom correspondence should be addressed. E-mail: martin.ulrich{at}mh-hannover.de.
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Abstract |
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Mouse and human embryonic stem cells (ESCs) have been shown to be able to efficiently differentiate towards cardiomyocytes (CMs). As murine and human ESCs do not allow for establishment of preclinical allogeneic transplantation models, it was aim of our study 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 rhesus monkey embryonic stem cell line R366.4, we were able to change this commitment and to direct generation of endodermal / mesodermal cells and further differentiation towards cardiomyocytes. Differentiation of RESCs resulted in an average of 18 % of spontaneously contracting embryoid bodies (EBs) from RESCs. Semiquantitative RT-PCR 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 multi electrode arrays (MEA) revealed evidence of functionality, electrical coupling and 
-adrenergic signaling of the generated cardiomyocytes.
This is the first study demonstrating generation of functional cardiomyocytes derived from RESCs. In contrast to human ES-cells, RESCs allow for establishment of preclinical allogeneic transplantation models. Moreover, RESC-derived cardiomyocytes represent a cell source for the development of high-throughput assays for cardiac safety pharmacology.
Key Words. Embryonic stem cells, differentiation, cardiomyocytes, primates
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