A Platform for Generation of Chamber-Specific Cardiac Tissues and Disease Modeling
Open accessAbstract
Tissue engineering using cardiomyocytes derived from human pluripotent stem cells holds a promise to revolutionize drug discovery, but only if limitations related to cardiac chamber specification and platform versatility can be overcome. We describe here a scalable tissue-cultivation platform that is cell source agnostic and enables drug testing under electrical pacing. The plastic platform enabled on-line noninvasive recording of passive tension, active force, contractile dynamics, and Ca 2+ transients, as well as endpoint assessments of action potentials and conduction velocity. By combining directed cell differentiation with electrical field conditioning, we engineered electrophysiologically distinct atrial and ventricular tissues with chamber-specific drug responses and gene expression. We report, for the first time, engineering of heteropolar cardiac tissues containing distinct atrial and ventricular ends, and we demonstrate their spatially confined responses to serotonin and ranolazine. Uniquely, electrical conditioning for up to 8 months enabled modeling of polygenic left ventricular hypertrophy starting from patient cells.
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Current state-of-the-art cardiac tissue models are well suited to measure contractile forces generated by cardiomyocytes, but modeling the cardiac pumping function using engineered cardiac tissues has been challenging.
“While current state-of-the-art cardiac tissue models are well suited to measure contractile forces generated by cardiomyocytes (11–13), modeling the cardiac pumping function using engineered cardiac tissues has been challenging.”
From Engineering a living cardiac pump on a chip using high-precision fabrication (2022) · cites this paper as [13]
Engineered cardiac tissues are being widely used as models to study drug toxicities and efficacy in vitro.
“Engineered cardiac tissues are being widely used as models to study drug toxicities and efficacy in vitro6,43–45,60.”
From 3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels (2021) · cites this paper as [43]
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A framework for developing sex-specific engineered heart models
Lock, R., Al Asafen, H., Fleischer, S., Tamargo, M., Zhao, Y., Radisic, M., & Vunjak-Novakovic, G. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00381-1 · Cited by 50 · see citing works
Self-citationMohammadi, M. H., Okhovatian, S., Savoji, H., Campbell, S. B., Lai, B. F. L., Wu, J., Pascual‐Gil, S., Bannerman, D., Rafatian, N., Li, R., et al. (2022) · Advanced Biology · doi:10.1002/adbi.202101165 · Cited by 28 · see citing works
Self-citation
- Authors
- Zhao, Y., Rafatian, N., Feric, N. T., Cox, B. J., Aschar-Sobbi, R., Wang, E. Y., Aggarwal, P., Zhang, B., Conant, G., Ronaldson-Bouchard, K., Pahnke, A., Protze, S., Lee, J. H., Davenport Huyer, L., Jekic, D., Wickeler, A., Naguib, H. E., Keller, G. M., Vunjak-Novakovic, G., Broeckel, U., Backx, P. H., & Radisic, M.
- Affiliations
- University of Toronto (CA)
- University Health Network (CA)
- Medical College of Wisconsin (US)
- Columbia University (US)
- Corresponding author
- Backx, Peter H.
- Radisic, Milica
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 176
- Issue
- 4
- Pages
- 913-927.e18
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6456036
- OpenAlex
- W2911534815
- Cited by
- 610
- References
- 60
- Citations by year
- 2026: 57 · 2025: 68 · 2024: 99 · 2023: 91 · 2022: 94 · 2021: 99 · 2020: 69 · 2019: 33
- FWCI
- 24.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Canadian Institutes of Health Research
- CIHR (MOP-126027, MOP-137107, MOP-142382)
- Natural Sciences and Engineering Research Council of Canada (RGPIN 326982-10)
- NSERC-CIHR Collaborative Health Research Grant (CHRP 493737-16)
- National Institutes of Health (2R01 HL076485, UG3 EB025765, P41 EB002520, U01 HL107437, R01 HL125580)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- cardiac tissue engineering, human pluripotent stem cell-derived cardiomyocytes, atrial tissue, ventricular tissue, disease modeling, left ventricular hypertrophy, drug testing, calcium transients, action potential, conduction velocity, serotonin, ranolazine
- MeSH terms
- Action Potentials, Cell Differentiation, Cells, Cultured, Humans, Models, Biological, Myocardium, Tissue Engineering, Myocytes, Cardiac, Pluripotent Stem Cells, Tissue Culture Techniques, Electrophysiological Phenomena, Induced Pluripotent Stem Cells
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