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Engineering Adolescence: Maturation of Human Pluripotent Stem Cell–Derived Cardiomyocytes
Open accessAbstract
The discovery of human pluripotent stem cells (hPSCs), including both human embryonic stem cells and human-induced pluripotent stem cells, has opened up novel paths for a wide range of scientific studies. The capability to direct the differentiation of hPSCs into functional cardiomyocytes has provided a platform for regenerative medicine, development, tissue engineering, disease modeling, and drug toxicity testing. Despite exciting progress, achieving the optimal benefits has been hampered by the immature nature of these cardiomyocytes. Cardiac maturation has long been studied in vivo using animal models; however, finding ways to mature hPSC cardiomyocytes is only in its initial stages. In this review, we discuss progress in promoting the maturation of the hPSC cardiomyocytes, in the context of our current knowledge of developmental cardiac maturation and in relation to in vitro model systems such as rodent ventricular myocytes. Promising approaches that have begun to be examined in hPSC cardiomyocytes include long-term culturing, 3-dimensional tissue engineering, mechanical loading, electric stimulation, modulation of substrate stiffness, and treatment with neurohormonal factors. Future studies will benefit from the combinatorial use of different approaches that more closely mimic nature’s diverse cues, which may result in broader changes in structure, function, and therapeutic applicability.
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“These values are comparable to those observed in tissues composed of immature cells where cell geometry, calcium handling, gap junction expression and spatial distribution, as well as other factors limit the conduction velocity when compared to mature tissues52,53.”
From A tissue-engineered scale model of the heart ventricle (2018) · cites this paper as [53]
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“Commonly, immature hPSC-CMs exhibit a positive chronotropic response to β-adrenergic stimulation but lack the positive inotropy characteristic of adult cardiomyocytes (Yang et al., 2014).”
From A human engineered mini-heart platform for mimicking ventricular pump function (2025) · cites this paper as Yang et al., 2014
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“However, these CMs are immature compared to their in vivo counterparts.”
From Single-cell RNA sequencing reveals maturation trajectory in human pluripotent stem cell-derived cardiomyocytes in engineered tissues (2023) · cites this paper as [10]
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“a number of major hallmarks have been regarded as a general consensus of the field, including myofibril maturation, electrophysiology, calcium handling, metabolic maturation, hypertrophy, and integration of physiology.10,37,38”
From Single-cell RNA sequencing reveals maturation trajectory in human pluripotent stem cell-derived cardiomyocytes in engineered tissues (2023) · cites this paper as [10]
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“Adult CMs are characterized by distinctive features including rod-like shape, polyploidy and organized myofibrils, mitochondrial networks, sarcoplasmic reticulum, and T-tubules.10,21”
From Single-cell RNA sequencing reveals maturation trajectory in human pluripotent stem cell-derived cardiomyocytes in engineered tissues (2023) · cites this paper as [10]
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“Biowire, with a more matured phenotype and a closer recapitulation of the adult native cardiac tissue, is considered to have more predictive power for cardiotoxicity screening [247].”
From Cardiovascular disease models: A game changing paradigm in drug discovery and screening (2019) · cites this paper as [247]
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Self-citation
Metadata
- Authors
- Yang, X., Pabon, L., & Murry, C. E.
- Affiliations
- University of Washington (US)
- Venue
- Circulation Research
- Published
- 2014-01-31
- Volume
- 114
- Issue
- 3
- Pages
- 511-523
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC3955370
- OpenAlex
- W2033765226
- Semantic Scholar
- d50fb63e8e68ab0d845e62dbf5f9c8c2470174d7
- Cited by
- 939
- References
- 128
- Citations by year
- 2026: 31 · 2025: 44 · 2024: 60 · 2023: 76 · 2022: 76 · 2021: 96 · 2020: 99 · 2019: 106 · 2018: 85 · 2017: 103 · 2016: 68 · 2015: 76 · 2014: 19
- FWCI
- 8.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (U01HL100405, P01HL094374, R01HL084642)
- National Institute of General Medical Sciences (P01GM081619)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- human pluripotent stem cells, cardiomyocyte maturation, human embryonic stem cells, induced pluripotent stem cells, cardiac differentiation, 3D tissue engineering, mechanical loading, electrical stimulation, substrate stiffness, neurohormonal factors, disease modeling, drug toxicity testing, regenerative medicine
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Genetic Engineering, Humans, Time Factors, Models, Animal, Myocytes, Cardiac, Pluripotent Stem Cells, Induced Pluripotent Stem Cells, Cell Engineering
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