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Electromechanical integration of cardiomyocytes derived from human embryonic stem cells

Nature Biotechnology volume 22, pages 1282–1289 (2004)Cite this article

Abstract

Cell therapy is emerging as a promising strategy for myocardial repair. This approach is hampered, however, by the lack of sources for human cardiac tissue and by the absence of direct evidence for functional integration of donor cells into host tissues. Here we investigate whether cells derived from human embryonic stem (hES) cells can restore myocardial electromechanical properties. Cardiomyocyte cell grafts were generated from hES cells in vitro using the embryoid body differentiating system. This tissue formed structural and electromechanical connections with cultured rat cardiomyocytes. In vivo integration was shown in a large-animal model of slow heart rate. The transplanted hES cell–derived cardiomyocytes paced the hearts of swine with complete atrioventricular block, as assessed by detailed three-dimensional electrophysiological mapping and histopathological examination. These results demonstrate the potential of hES-cell cardiomyocytes to act as a rate-responsive biological pacemaker and for future myocardial regeneration strategies.

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Figure 1: Morphological and functional characterization of the hES cardiomyocytes.
Figure 2: Functional integration in the cocultures.
Figure 3: Persistent electromechanical coupling in the cocultures.
Figure 4: ECG recordings in one of the animals with complete atrioventricular block.
Figure 5: Electroanatomical mapping and pathological correlation of the new ectopic rhythm.
Figure 6: Histological examination of the site of earliest electrical activation.

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Acknowledgements

We thank Asaf Zaretzki and Edith Cohen for their valuable help in the animal studies. We thank Ofer Shenker and the interdisciplinary unit for their technical assistance. This research was supported in part by the Israel Science Foundation (grant no. 520/01), by the Israel Health Ministry, by the Johnson & Johnson Focused Research Grant and by the Nahum Guzik Research Fund.

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Authors and Affiliations

  1. Department of Biophysics and Physiology, The Sohnis Family Research Laboratory for the Regeneration of Functional Myocardium, the Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, P.O. Box 9649, Haifa, Israel

    Izhak Kehat, Leonid Khimovich, Oren Caspi, Amira Gepstein, Rona Shofti, Gil Arbel, Irit Huber & Lior Gepstein

  2. The Rappaport Family Institute for Research in the Medical Sciences,

    Lior Gepstein

  3. Department of Cardiology, Rambam Medical Center, Haifa, 31096, Israel

    Izhak Kehat & Lior Gepstein

  4. Department of Obstetrics and Gynecology, Rambam Medical Center, Haifa, 31096, Israel

    Joseph Itskovitz-Eldor

  5. Department of Physiology, University of Kentucky College of Medicine, Lexington, 40536-0298, Kentucky, USA

    Jonathan Satin

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  1. Izhak Kehat
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Supplementary information

Supplementary Movie

A movie showing a typical coculture grown on top of the MEA plate. The image is shown at a high magnification ('40). Note the synchronous contractions of the hES cell–derived cardiomyocyte tissue (cell cluster on the right side of the image) and the neonatal rat ventricular myocyte monolayer. (MOV 314 kb)

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Kehat, I., Khimovich, L., Caspi, O. et al. Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat Biotechnol 22, 1282–1289 (2004). https://doi.org/10.1038/nbt1014

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