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.
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Key genes in the maturation of fatty acid metabolism, sarcomere, and ion channels were upregulated in cardiomyocytes from hvCTS and hvCOC relative to those from CS and hvCAS.
“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]
The gene-expression passage in our copy (labelled Abstract; page unavailable) reports increases in genes associated with cardiac energetics, ultrastructure, and conduction, supporting the general maturation point. It compares early/intensity-trained tissues with other training and developmental groups, not cardiomyocytes from hvCTS and hvCOC with those from CS and hvCAS. The claimed group-specific comparison is therefore unsupported by this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe hierarchical organization of cardiac tissues is needed to regulate the spatiotemporal dynamics of excitation-contraction coupling that produce the cardiac cycle.
“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]
Cardiac tissue engineering can provide a unique cellular niche environment to promote in vitro maturation of differentiated cardiomyocytes.
“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]
Fibrillar hydrogels such as collagen and fibrin are compatible with cardiac tissue engineering because cells can rapidly contract the matrix to form high cell density tissues.
“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]
The structure and function of iPSC-CMs can be matured using mechanical and electrical stimulation, prolonged culture periods, and co-culture in the presence of CFs or endothelial cells.
“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]
The sarcomere length of 17-day-old CMs in LVD-cardiac 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).
“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]
Tissue engineering approaches for heart-on-a-chip or heart organoid models allow high control of the end construct but tend to be expensive, work-intensive, and not readily scalable.
“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]
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- 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
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