Engineering Adolescence: Maturation of Human Pluripotent Stem Cell–Derived Cardiomyocytes

Yang, Xiulan; Pabon, Lil; Murry, Charles E.

doi:10.1161/circresaha.114.300558

Cited by 939Pluripotent Stem Cells ResearchTissue Engineering and Regenerative MedicineCongenital heart defects research

Engineering Adolescence: Maturation of Human Pluripotent Stem Cell–Derived Cardiomyocytes

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Yang, Xiulan, Pabon, Lil, Murry, Charles E.·2014·Circulation Research

DOI 10.1161/circresaha.114.300558PMC PMC3955370

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Abstract

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 propagation velocities are comparable to those observed in tissues composed of immature cells where cell geometry, calcium handling, gap junction expression and spatial distribution limit conduction velocity compared to mature tissues.
“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]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
Immature hPSC-CMs commonly exhibit a positive chronotropic response to β-adrenergic stimulation but lack the positive inotropy characteristic of adult cardiomyocytes.
“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
In “Responses to Calcium and Beta-Adrenergic Stimulation,” the review reports a pronounced chronotropic response without significant inotropy in one hESC-CM study. But it also reports inotropic responses in other hPSC-CM studies and says the discrepancy is unresolved, so it does not establish that immature hPSC-CMs commonly lack positive inotropy. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) are immature compared to their in vivo counterparts.
“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]
Major hallmarks regarded as a general consensus of cardiomyocyte maturation include myofibril maturation, electrophysiology, calcium handling, metabolic maturation, hypertrophy, and integration of physiology.
“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]
Adult cardiomyocytes are characterized by rod-like shape, polyploidy, organized myofibrils, mitochondrial networks, sarcoplasmic reticulum, and T-tubules.
“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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[80]Lundy SDZW Regnier M Laflamme M Structural and functional maturation of cardiomyocytes derived from human pluripotent stem cells Stem Cells Dev 2013 PMC3699903 23461462

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Authors: Yang, X., Pabon, L., & Murry, C. E.
Affiliations: University of Washington (US)
ORCID: Pabon, Lil
Murry, Charles E.
Venue: Circulation Research
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2014-01-31
Volume: 114
Issue: 3
Pages: 511-523
ISSN: 0009-7330 (ISSN-L)
1524-4571
DOI: 10.1161/circresaha.114.300558
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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Engineering Adolescence: Maturation of Human Pluripotent Stem Cell–Derived Cardiomyocytes

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