The DOI matches its Crossref record; 36 of the 36 references it cites were found in a registry or an index.
Mechanism of spontaneous excitability in human embryonic stem cell derived cardiomyocytes
Open accessAbstract
Human embryonic stem cell‐derived cardiomyocytes (hES‐CMs) are thought to recapitulate the embryonic development of heart cells. Given the exciting potential of hES‐CMs as replacement tissue in diseased hearts, we investigated the pharmacological sensitivity and ionic current of mid‐stage hES‐CMs (20–35 days post plating). A high‐resolution microelectrode array was used to assess conduction in multicellular preparations of hES‐CMs in spontaneously contracting embryoid bodies (EBs). TTX (10 μ m) dramatically slowed conduction velocity from 5.1 to 3.2 cm s−1 while 100 μ m TTX caused complete cessation of spontaneous electrical activity in all EBs studied. In contrast, the Ca 2+ channel blockers nifedipine or diltiazem (1 μ m) had a negligible effect on conduction. These results suggested a prominent Na+ channel current, and therefore we patch‐clamped isolated cells to record Na+ current and action potentials (APs). We found for isolated hES‐CMs a prominent Na+ current (244 ± 42 pA pF−1 at 0 mV; n= 19), and a hyperpolarization‐activated current (HCN), but no inward rectifier K+ current. In cell clusters, 3 μ m TTX induced longer AP interpulse intervals and 10 μ m TTX caused cessation of spontaneous APs. In contrast nifedipine (Ca 2+ channel block) and 2 m m Cs+ (HCN complete block) induced shorter AP interpulse intervals. In single cells, APs stimulated by current pulses had a maximum upstroke velocity (d V/d tmax) of 118 ± 14 V s−1 in control conditions; in contrast, partial block of Na+ current significantly reduced stimulated d V/d tmax (38 ± 15 V s−1). RT‐PCR revealed Na V 1.5, Ca V 1.2, and HCN‐2 expression but we could not detect Kir2.1. We conclude that hES‐CMs at mid‐range development express prominent Na+ current. The absence of background K+ current creates conditions for spontaneous activity that is sensitive to TTX in the same range of partial block of Na V 1.5; thus, the Na V 1.5 Na+ channel is important for initiating spontaneous excitability in hES‐derived heart cells.
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Cites
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Cited by
Ma, J., Guo, L., Fiene, S. J., Anson, B. D., Thomson, J. A., Kamp, T. J., Kolaja, K. L., Swanson, B. J., & January, C. T. (2011) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00694.2011 · Cited by 770
Structural and Functional Maturation of Cardiomyocytes Derived from Human Pluripotent Stem Cells
Lundy, S. D., Zhu, W.-Z., Regnier, M., & Laflamme, M. A. (2013) · Stem Cells and Development · doi:10.1089/scd.2012.0490 · Cited by 738
Caspi, O., Huber, I., Kehat, I., Habib, M., Arbel, G., Gepstein, A., Yankelson, L., Aronson, D., Beyar, R., & Gepstein, L. (2007) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2007.07.054 · Cited by 573
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Characterization and culture of human embryonic stem cells
Hoffman, L. M., & Carpenter, M. K. (2005) · Nature Biotechnology · doi:10.1038/nbt1102 · Cited by 465
Metadata
- Authors
- Satin, J., Kehat, I., Caspi, O., Huber, I., Arbel, G., Itzhaki, I., Magyar, J., Schroder, E. A., Perlman, I., & Gepstein, L.
- Venue
- The Journal of Physiology
- Publisher
- Wiley
- Published
- 2004-08-25
- Volume
- 559
- Issue
- 2
- Pages
- 479-496
- ISSN
- 0022-3751 (ISSN-L)
- 1469-7793
- OpenAlex
- W1530324520
- Cited by
- 283
- References
- 36
- FWCI
- 10.53
- Type
- journal article
- Language
- en
- Open access
- green
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- Satin, J., Kehat, I., Caspi, O., Huber, I., Arbel, G., Itzhaki, I., Magyar, J., Schroder, E. A., Perlman, I., & Gepstein, L. (2004). Mechanism of spontaneous excitability in human embryonic stem cell derived cardiomyocytes. The Journal of Physiology. https://doi.org/10.1113/jphysiol.2004.068213
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