Tissue-engineered cardiac patch for advanced functional maturation of human ESC-derived cardiomyocytes
Open accessAbstract
Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) provide a promising source for cell therapy and drug screening. Several high-yield protocols exist for hESC-CM production; however, methods to significantly advance hESC-CM maturation are still lacking. Building on our previous experience with mouse ESC-CMs, we investigated the effects of 3-dimensional (3D) tissue-engineered culture environment and cardiomyocyte purity on structural and functional maturation of hESC-CMs. 2D monolayer and 3D fibrin-based cardiac patch cultures were generated using dissociated cells from differentiated Hes2 embryoid bodies containing varying percentage (48-90%) of CD172a (SIRPA)-positive cardiomyocytes. hESC-CMs within the patch were aligned uniformly by locally controlling the direction of passive tension. Compared to hESC-CMs in age (2 weeks) and purity (48-65%) matched 2D monolayers, hESC-CMs in 3D patches exhibited significantly higher conduction velocities (CVs), longer sarcomeres (2.09 ± 0.02 vs. 1.77 ± 0.01 μm), and enhanced expression of genes involved in cardiac contractile function, including cTnT, αMHC, CASQ2 and SERCA2. The CVs in cardiac patches increased with cardiomyocyte purity, reaching 25.1 cm/s in patches constructed with 90% hESC-CMs. Maximum contractile force amplitudes and active stresses of cardiac patches averaged to 3.0 ± 1.1 mN and 11.8 ± 4.5 mN/mm(2), respectively. Moreover, contractile force per input cardiomyocyte averaged to 5.7 ± 1.1 nN/cell and showed a negative correlation with hESC-CM purity. Finally, patches exhibited significant positive inotropy with isoproterenol administration (1.7 ± 0.3-fold force increase, EC50 = 95.1 nm). These results demonstrate highly advanced levels of hESC-CM maturation after 2 weeks of 3D cardiac patch culture and carry important implications for future drug development and cell therapy studies.
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Engineered tissues for in vitro use may not need physiologic function levels to be predictive, if they recapitulate cardiac-appropriate responses to treatments.
“However, in contrast to constructs designed for surgical implantation [8], engineered tissues designed for in vitro applications, such as our organoids, may not require physiologic levels of function to be predictive and impactful, provided they can recapitulate cardiac-appropriate responses to treatments and interventions of interest.”
From Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells (2018) · cites this paper as [8]
The Conclusion (page unavailable) identifies the engineered cardiac patch as a platform for future cell-based cardiac therapies, supporting its use as an example of a therapeutically oriented construct. It does not say the patch was designed for surgical implantation. The sentence’s assertion that in vitro tissues may be predictive without physiologic function levels is the citing authors’ contrast, not a finding attributed to this source by the placement of [8]. (LLM, conf=0.78)
Experimental — accuracy not yet measuredPrior studies have arranged hPSC-derived ventricular cardiomyocytes as monolayers and patches for electrophysiology and for surgical implantation.
“Although hPSC-vCMs have been organized as monolayers and patches for electrophysiological assessment [6–8] and even surgical engraftment [9–11]”
From Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells (2018) · cites this paper as [8]
Engineered tissues with contractile forces and conduction properties approaching native myocardium have been reported by several groups.
“A number of groups have reported engineered tissues with contractile forces and conduction properties approaching physiologic levels observed in native myocardium [8,13,31,32].”
From Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells (2018) · cites this paper as [8]
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- Authors
- Zhang, D., Shadrin, I. Y., Lam, J., Xian, H.-Q., Snodgrass, H. R., & Bursac, N.
- Affiliations
- Duke University (US)
- VistaGen Therapeutics (United States) (US)
- Corresponding author
- Bursac, Nenad
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 34
- Issue
- 23
- Pages
- 5813-5820
- ISSN
- 0142-9612 (ISSN-L)
- PMC
- PMC3660435
- OpenAlex
- W2141241503
- Cited by
- 565
- References
- 42
- Citations by year
- 2026: 14 · 2025: 21 · 2024: 25 · 2023: 27 · 2022: 43 · 2021: 53 · 2020: 59 · 2019: 54 · 2018: 47 · 2017: 61 · 2016: 58 · 2015: 46 · 2014: 40 · 2013: 17
- FWCI
- 52.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Biomaterials (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DukeSpace (Duke University) (submittedVersion)
- Funders
- National Institutes of Health (UH2TR000505, 5r01hl104326-05)
- National Heart, Lung, and Blood Institute (R01-HL104326, R21HL095069)
- National Institute of General Medical Sciences (T32GM007171)
- National Center for Advancing Translational Sciences
- Common Fund
- Topics
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- human embryonic stem cell-derived cardiomyocytes, cardiomyocyte maturation, SIRPα, cardiomyocyte alignment, conduction velocity, sarcomere length, contractile force, inotropic effect, isoproterenol, cardiac contractile function
- MeSH terms
- Action Potentials, Animals, Cardiotonic Agents, Cell Line, Gene Expression Regulation, Humans, Myocardial Contraction, Phenotype, Receptors, Adrenergic, beta, Time Factors, Tissue Engineering, Myocytes, Cardiac, Mice, Embryonic Stem Cells, Tissue Scaffolds
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