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EMBRYONIC STEM CELLS |
aLaboratory of Stem Cell Differentiation, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan;
bFirst Department of Surgery, University of Toyama Graduate School of Medicine, Toyama, Japan;
cDepartment of Physiology, Faculty of Medicine, Jichi Medical University, Tochigi, Japan;
dDepartment of Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;
ePRESTO, Japan Science and Technology Agency, Tokyo, Japan
Key Words. In vitro differentiation • Embryonic stem cells • Stroma cells • Stem/progenitor cells • Differentiation • Tissue regeneration
Correspondence: Jun K. Yamashita, M.D., Ph.D., Laboratory of Stem Cell Differentiation, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. Telephone: +81-75-751-3853; Fax: +81-75-751-4824; e-mail: juny{at}frontier.kyoto-u.ac.jp
Received June 26, 2006;
accepted for publication July 22, 2007.
Disclosure of potential conflicts of interest is found at the end of this article.
First published online in STEM CELLS EXPRESS July 26, 2007.
Regeneration of cardiac pacemakers is an important target of cardiac regeneration. Previously, we developed a novel embryonic stem (ES) cell differentiation system that could trace cardiovascular differentiation processes at the cellular level. In the present study, we examine expressions and functions of ion channels in ES cell-derived cardiomyocytes during their differentiation and identify ion channels that confer their automaticity. ES cell-derived Flk1+ mesoderm cells give rise to spontaneously beating cardiomyocytes on OP9 stroma cells. Spontaneously beating colonies observed at day 9.5 of Flk1+ cell culture (Flk-d9.5) were significantly decreased at Flk-d23.5. Expressions of ion channels in pacemaker cells hyperpolarization-activated cyclic nucleotide-gated (HCN)1 and -4 and voltage-gated calcium channel (Cav)3.1 and -3.2 were significantly decreased in purified cardiomyocytes at Flk-d23.5 compared with at Flk-d9.5, whereas expression of an atrial and ventricular ion channel, inward rectifier potassium channel (Kir)2.1, did not change. Blockade of HCNs and Cav ion channels significantly inhibited beating rates of cardiomyocyte colonies. Electrophysiological studies demonstrated that spontaneously beating cardiomyocytes at Flk-d9.5 showed almost similar features to those of the native mouse sinoatrial node except for relatively deep maximal diastolic potential and faster maximal upstroke velocity. Although 
60% of myocytes at Flk-d23.5 revealed almost the same properties as those at Flk-d9.5, 40% of myocytes showed loss of HCN and decreased Cav3 currents and ceased spontaneous beating, with no remarkable increase of Kir2.1. Thus, HCN and Cav3 ion channels should be responsible for the maintenance of automaticity in ES cell-derived cardiomyocytes. Controlled regulation of these ion channels should be required to generate complete biological pacemakers.
This article has been cited by other articles:
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  G. Narazaki, H. Uosaki, M. Teranishi, K. Okita, B. Kim, S. Matsuoka, S. Yamanaka, and J. K. Yamashita Directed and Systematic Differentiation of Cardiovascular Cells From Mouse Induced Pluripotent Stem Cells Circulation, July 29, 2008; 118(5): 498 - 506. [Abstract] [Full Text] [PDF]
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