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EMBRYONIC STEM CELLS: CHARACTERIZATION SERIES

Bone Morphogenetic Protein-4 Enhances Cardiomyocyte Differentiation of Cynomolgus Monkey ESCs in Knockout Serum Replacement Medium

^aDepartment of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
^bInternational Center for Young Scientists and
^eBiomaterials Center, National Institute for Materials Science, Tsukuba, Ibaraki, Japan;
^cHarvard-Massachusetts Institute of Technology Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA;
^dCenter for Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, Massachusetts, USA;
^fInstitute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan;
^gCardiovascular Institute, Mount Sinai Medical School, New York, New York, USA

Key Words. Embryonic stem cells • Differentiation • Bone morphogenic protein • Primate

Correspondence: Hossein Hosseinkhani, Ph.D., D. Med. Sci., International Center for Young Scientists, National Institute for Materials Science, Tsukuba, Ibaraki, 305-0044, Japan. Telephone: 81-29-851-3354; Fax: 81-29-860-4706; e-mail: hossein.hosseinkhani{at}nims.go.jp

Received April 15, 2006; accepted for publication November 14, 2006.
First published online in STEM CELLS EXPRESS   November 30, 2006.



Despite extensive research in the differentiation of rodent ESCs into cardiomyocytes, there have been few studies of this process in primates. In this study, we examined the role of bone morphogenic protein-4 (BMP-4) to induce cardiomyocyte differentiation of cynomolgus monkey ESCs. To study the role of BMP-4, EBs were formed and cultured in Knockout Serum Replacement (KSR) medium containing BMP-4 for 8 days and subsequently seeded in gelatin-coated dishes for 20 days. It was found that ESCs differentiated into cardiomyocytes upon stimulation with BMP-4 in KSR medium, which resulted in a large fraction of beating EBs (16%) and the upregulation of cardiac-specific proteins in a dose and time-dependent manner. In contrast, the addition of BMP-4 in FBS-containing medium resulted in a lower fraction of beating EBs (6%). BMP-4 acted principally between mesendodermal and mesoderm progenitors and subsequently enhanced their expression. Ultrastructural observation revealed that beating EBs contained mature cardiomyocytes with sarcomeric structures. In addition, immunostaining, reverse transcription-polymerase chain reaction, and Western blotting for cardiac markers confirmed the increased differentiation of cardiomyocytes in these cultures. Moreover, electrophysiological studies demonstrated that the differentiated cardiomyocytes were electrically activated. These findings may be useful in developing effective culture conditions to differentiate cynomolgus monkey ESCs into cardiomyocytes for studying developmental biology and for regenerative medicine.

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