The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
Advanced maturation of human cardiac tissue grown from pluripotent stem cells
Open accessAbstract
Cardiac tissues generated from human induced pluripotent stem cells (iPSCs) can serve as platforms for patient-specific studies of physiology and disease1–6. However, the predictive power of these models is presently limited by the immature state of the cells1,2,5,6. Here we show that this fundamental limitation can be overcome if cardiac tissues are formed from early-stage iPSC-derived cardiomyocytes soon after the initiation of spontaneous contractions and are subjected to physical conditioning with increasing intensity over time. After only four weeks of culture, for all iPSC lines studied, such tissues displayed adult-like gene expression profiles, remarkably organized ultrastructure, physiological sarcomere length (2.2 µm) and density of mitochondria (30%), the presence of transverse tubules, oxidative metabolism, a positive force–frequency relationship and functional calcium handling. Electromechanical properties developed more slowly and did not achieve the stage of maturity seen in adult human myocardium. Tissue maturity was necessary for achieving physiological responses to isoproterenol and recapitulating pathological hypertrophy, supporting the utility of this tissue model for studies of cardiac development and disease. A tissue culture system that provides an increasing intensity of electromechanical stimulation over time enables an in vitro model of cardiac tissue derived from human induced pluripotent stem cells to develop many of the characteristics of adult cardiac tissue.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“While these approaches allow for high control of the end construct, they tend to be expensive, work-intensive, and not readily scalable.”
From Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease (2021) · cites this paper as [12]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Key genes in the maturation of fatty acid metabolism, sarcomere, and ion channels were also upregulated in CMs from the hvCTS and hvCOC relative to those from the CS and hvCAS (Figure 3C).11,23,36”
From Single-cell RNA sequencing reveals maturation trajectory in human pluripotent stem cell-derived cardiomyocytes in engineered tissues (2023) · cites this paper as [11]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“This is particularly important in the heart, where the hierarchical organization of cardiac tissues3 is needed to regulate the spatiotemporal dynamics of excitation-contraction coupling, resulting in the cardiac cycle4, 5.”
From Fibre-infused gel scaffolds guide cardiomyocyte alignment in 3D-printed ventricles (2023) · cites this paper as [4]
The cited source says what the claim attributes to it.
In the citing paper
“cardiac tissue engineering can provide a unique cellular niche environment to promote in vitro maturation of differentiated CMs.11,12,13,14,15,16,17,18”
From Single-cell RNA sequencing reveals maturation trajectory in human pluripotent stem cell-derived cardiomyocytes in engineered tissues (2023) · cites this paper as [11]
In the citing paper
“Fibrillar hydrogels such as collagen and fibrin are compatible with cardiac tissue engineering as the cells can rapidly contract the matrix to form high cell density tissues49”
From 3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels (2021) · cites this paper as [49]
In the citing paper
“The structure and function of iPSC-CMs can be matured using mechanical and electrical stimulation42,49, prolonged culture periods64,65, and also co-culture in the presence of CFs or endothelial cells66.”
From 3D bioprinting of high cell-density heterogeneous tissue models through spheroid fusion within self-healing hydrogels (2021) · cites this paper as [49]
In the citing paper
“The sarcomere length of the 17-day-old CMs in LVDcardiac tissues displayed a statistically significant increase compared with that of day 3, extended from ~1.74 µm to ~2.02 µm, whose value was quite close to that in adult human CMs (2.2 µm) 42 (Fig. 5j).”
From Leaf-venation-directed cellular alignment for macroscale cardiac constructs with tissue-like functionalities (2023) · cites this paper as [42]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Cardiac excitation–contraction coupling
Bers, D., & Despa, S. (2002) · Nature · doi:10.1038/415198a · Cited by 4,927
Biowire: a platform for maturation of human pluripotent stem cell–derived cardiomyocytes
Nunes, S. S., Miklas, J. W., Liu, J., Aschar-Sobbi, R., Xiao, Y., Zhang, B., Jiang, J., Massé, S., Gagliardi, M., Hsieh, A., et al. (2013) · Nature Methods · doi:10.1038/nmeth.2524 · Cited by 952
Engineering Adolescence: Maturation of Human Pluripotent Stem Cell–Derived Cardiomyocytes
Yang, X., Pabon, L., & Murry, C. E. (2014) · Circulation Research · doi:10.1161/circresaha.114.300558 · Cited by 939
Radisic, M., Park, H., Shing, H., Consi, T. R., Schöen, F. J., Langer, R., Freed, L. E., & Vunjak‐Novakovic, G. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407817101 · Cited by 929
Self-citationWang, G., McCain, M. L., Yang, L., He, A., Pasqualini, F. S., Agarwal, A., Yuan, H., Jiang, D., Zhang, D., Zangi, L., et al. (2014) · Nature Medicine · doi:10.1038/nm.3545 · Cited by 837
Ma, J., Guo, L., Fiene, S., 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 787
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
Using induced pluripotent stem cells to investigate cardiac phenotypes in Timothy syndrome
Yazawa, M., Hsueh, B., Jia, X., Pasca, A. M., Bernstein, J. A., Hallmayer, J., & Dolmetsch, R. E. (2011) · Nature · doi:10.1038/nature09855 · Cited by 677
Self-citationGrowth of engineered human myocardium with mechanical loading and vascular coculture
Tulloch, N. L., Muskheli, V., Razumova, M. V., Korte, F. S., Regnier, M., Hauch, K. D., Pabon, L., Reinecke, H., & Murry, C. E. (2011) · Circulation Research · doi:10.1161/circresaha.110.237206 · Cited by 666
Lopaschuk, G. D., & Jaswal, J. S. (2010) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e3181e74a14 · Cited by 636
Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells
Chung, S. S., Dzeja, P. P., Faustino, R. S., Pérez-Terzic, C. M., Behfar, A., & Terzic, A. (2007) · Nature Clinical Practice Cardiovascular Medicine · doi:10.1038/ncpcardio0766 · Cited by 514
Induced pluripotent stem cells: the new patient?
Bellin, M., Marchetto, M. C., Gage, F. H., & Mummery, C. L. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3448 · Cited by 454
Parkin-mediated mitophagy directs perinatal cardiac metabolic maturation in mice
Gong, G., Song, M., Csordás, G., Kelly, D. P., Matkovich, S. J., & Dorn, G. W. (2015) · Science · doi:10.1126/science.aad2459 · Cited by 451
Shadrin, I. Y., Allen, B. W., Qian, Y., Jackman, C. P., Carlson, A. L., Juhas, M. E., & Bursac, N. (2017) · Nature Communications · doi:10.1038/s41467-017-01946-x · Cited by 420
Human Engineered Heart Tissue: Analysis of Contractile Force
Mannhardt, I., Breckwoldt, K., Letuffe-Brenière, D., Schaaf, S., Schulz, H., Neuber, C., Benzin, A., Werner, T., Eder, A., Schulze, T., et al. (2016) · Stem Cell Reports · doi:10.1016/j.stemcr.2016.04.011 · Cited by 398
T-Tubule Function in Mammalian Cardiac Myocytes
Brette, F., & Orchard, C. H. (2003) · Circulation Research · doi:10.1161/01.res.0000074908.17214.fd · Cited by 389
Maturing human pluripotent stem cell-derived cardiomyocytes in human engineered cardiac tissues
Feric, N. T., & Radisic, M. (2016) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2015.04.019 · Cited by 247
Cardiac BIN1 folds T-tubule membrane, controlling ion flux and limiting arrhythmia
Hong, T., Yang, H., Zhang, S.-S., Cho, H. C., Kalashnikova, M., Sun, B., Zhang, H., Bhargava, A., Grabe, M., Olgin, J. E., et al. (2014) · Nature Medicine · doi:10.1038/nm.3543 · Cited by 245
Miniaturized iPS-Cell-Derived Cardiac Muscles for Physiologically Relevant Drug Response Analyses
Huebsch, N., Loskill, P., Deveshwar, N., Spencer, C. I., Judge, L. M., Mandegar, M. A., Fox, C. B., Mohamed, T., Ma, Z., Mathur, A., et al. (2016) · Scientific Reports · doi:10.1038/srep24726 · Cited by 236
Human Stem Cells for Modeling Heart Disease and for Drug Discovery
Matsa, E., Burridge, P. W., & Wu, J. C. (2014) · Science Translational Medicine · doi:10.1126/scitranslmed.3008921 · Cited by 217
Ribeiro, M. C., Tertoolen, L. G., Guadix, J. A., Bellin, M., Kosmidis, G., D'Aniello, C., Monshouwer-Kloots, J., Goumans, M.-J., Wang, Y.-L., Feinberg, A. W., et al. (2015) · Biomaterials · doi:10.1016/j.biomaterials.2015.01.067 · Cited by 214
Generation of Functional Ventricular Heart Muscle from Mouse Ventricular Progenitor Cells
Domian, I. J., Chiravuri, M., van der Meer, P., Feinberg, A. W., Shi, X., Shao, Y., Wu, S. M., Parker, K. K., & Chien, K. R. (2009) · Science · doi:10.1126/science.1177350 · Cited by 209
Dynamic culture yields engineered myocardium with near-adult functional output
Jackman, C. P., Carlson, A. L., & Bursac, N. (2016) · Biomaterials · doi:10.1016/j.biomaterials.2016.09.024 · Cited by 193
Hasenfuss, G. P., Mulieri, L. A., Blanchard, E. M., Holubarsch, C., Leavitt, B. J., Ittleman, F. P., & Alpert, N. R. (1991) · Circulation Research · doi:10.1161/01.res.68.3.836 · Cited by 185
Autonomous beating rate adaptation in human stem cell-derived cardiomyocytes
Eng, G. M., Lee, B. W., Protas, L., Gagliardi, M., Brown, K. R., Kass, R. S., Keller, G. M., Robinson, R. B., & Vunjak‐Novakovic, G. (2016) · Nature Communications · doi:10.1038/ncomms10312 · Cited by 178
Self-citationBioenergetics, mitochondria, and cardiac myocyte differentiation
Porter, G. A., Hom, J. R., Hoffman, D. L., Quintanilla, R. A., Bentley, K. L. D. M., & Sheu, S.-S. (2011) · Progress in Pediatric Cardiology · doi:10.1016/j.ppedcard.2011.02.002 · Cited by 154
Maintaining Ancient Organelles
Vega, R. B., Horton, J. L., & Kelly, D. P. (2015) · Circulation Research · doi:10.1161/circresaha.116.305420 · Cited by 147
Kaprielian, R., Stevenson, S. A., ROTHERY, S. M., Cullen, M. J., & Severs, N. J. (2000) · Circulation · doi:10.1161/01.cir.101.22.2586 · Cited by 141
Force Frequency Relationship of the Human Ventricle Increases During Early Postnatal Development
Wiegerinck, R. F., Cojoc, A., Zeidenweber, C. M., Ding, G., Shen, M., Joyner, R. W., Fernandez, J. D., Kanter, K. R., Kirshbom, P. M., Kogon, B. E., et al. (2009) · Pediatric Research · doi:10.1203/pdr.0b013e318199093c · Cited by 90
Mitochondria shape cardiac metabolism
Gottlieb, R. A., & Bernstein, D. (2015) · Science · doi:10.1126/science.aad8222 · Cited by 36
Sun, R. R., Bouchard, M. B., & Hillman, E. M. C. (2010) · Biomedical Optics Express · doi:10.1364/boe.1.000385 · Cited by 24
Nanoscale three-dimensional imaging of the human myocyte
Sulkin, M. S., Yang, F., Holzem, K. M., Leer, B. V., Bugge, C., Laughner, J. I., Green, K., & Efimov, I. R. (2014) · Journal of Structural Biology · doi:10.1016/j.jsb.2014.08.005 · Cited by 19
Morikawa, K., Song, L., Ronaldson-Bouchard, K., Vunjak‐Novakovic, G., & Yazawa, M. (2018) · Protocol Exchange · doi:10.1038/protex.2018.030 · Cited by 1
Self-citation
Cited by
Sorted by citations
A guide to the organ-on-a-chip
Leung, C. M., de Haan, P., Ronaldson-Bouchard, K., Kim, G.-A., Ko, J., Rho, H. S., Chen, Z., Habibovic, P., Jeon, N. L., Takayama, S., et al. (2022) · Nature Reviews Methods Primers · doi:10.1038/s43586-022-00118-6 · Cited by 1,116
Self-citationOrgans-on-chips: into the next decade
Low, L. A., Mummery, C., Berridge, B. R., Austin, C. P., & Tagle, D. A. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0079-3 · Cited by 1,029
Cardiomyocyte maturation: advances in knowledge and implications for regenerative medicine
Karbassi, E., Fenix, A. M., Marchianò, S., Muraoka, N., Nakamura, K., Yang, X., & Murry, C. E. (2020) · Nature Reviews Cardiology · doi:10.1038/s41569-019-0331-x · Cited by 796
Induced pluripotent stem cells in disease modelling and drug discovery
Rowe, R. G., & Daley, G. Q. (2019) · Nature Reviews Genetics · doi:10.1038/s41576-019-0100-z · Cited by 704
Cardiomyocyte Maturation: New Phase in Development
Guo, Y., & Pu, W. T. (2020) · Circulation Research · doi:10.1161/circresaha.119.315862 · Cited by 653
Metadata
- Authors
- Ronaldson-Bouchard, K., Ma, S. P., Yeager, K., Chen, T., Song, L., Sirabella, D., Morikawa, K., Teles, D., Yazawa, M., & Vunjak-Novakovic, G.
- Affiliations
- Columbia University (US)
- Columbia University Irving Medical Center (US)
- ORCID
- Venue
- Nature
- Published
- 2018-04
- Volume
- 556
- Issue
- 7700
- Pages
- 239-243
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5895513
- OpenAlex
- W2794616878
- Semantic Scholar
- 5d586dd663580dea97fa99d0561d694f4f7165cc
- Cited by
- 1,272
- References
- 33
- Citations by year
- 2026: 122 · 2025: 130 · 2024: 138 · 2023: 150 · 2022: 158 · 2021: 196 · 2020: 179 · 2019: 142 · 2018: 55
- FWCI
- 50.60
- Type
- journal article
- Language
- en
- Update notices
- correction (2019-07-31)
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, other-oa)
- Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) (submittedVersion, cc-by-nc-nd)
- Funders
- Universidade do Minho
- National Institutes of Health (2r01hl076485-16, EB 17103, HL076485, EB025765)
- Japan Society for the Promotion of Science
- National Heart, Lung, and Blood Institute (R01HL138486, R01-HL076485, HL076485)
- National Institute of Environmental Health Sciences
- National Institute of Arthritis and Musculoskeletal and Skin Diseases
- National Institute of Biomedical Imaging and Bioengineering (EB025765, UG3EB025765, UH3EB017103, UH3EB025765, P41EB002520)
- National Institute of Dental and Craniofacial Research
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- iPSC-derived cardiomyocytes, induced pluripotent stem cells, electromechanical stimulation, physical conditioning, cardiac hypertrophy, isoproterenol response, calcium handling, sarcomere length, mitochondrial density, T-tubules, force-frequency relationship, patient-specific cardiac models
- MeSH terms
- Adult, Calcium, Cell Differentiation, Energy Metabolism, Heart, Humans, Isoproterenol, Mitochondria, Myocardium, Sarcomeres, Myocytes, Cardiac, Tissue Culture Techniques, Induced Pluripotent Stem Cells, Transcriptome
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
