Mechanism-based facilitated maturation of human pluripotent stem cell-derived cardiomyocytes
Open accessAbstract
Background—: Human embryonic stem cells (hESCs) can be efficiently and reproducibly directed into cardiomyocytes (CMs) using stage-specific induction protocols. However, their functional properties and suitability for clinical and other applications have not been evaluated. Methods and Results—: Here we showed that CMs derived from multiple pluripotent human stem cell lines (hESC: H1, HES2) and types (induced pluripotent stem cell) using different in vitro differentiation protocols (embryoid body formation, endodermal induction, directed differentiation) commonly displayed immature, proarrhythmic action potential properties such as high degree of automaticity, depolarized resting membrane potential, Phase 4- depolarization, and delayed after-depolarization. Among the panoply of sarcolemmal ionic currents investigated ( I Na + / I CaL + / I Kr + / I NCX + / I f + / I to + / I K1 − / I Ks − ), we pinpointed the lack of the Kir2.1-encoded inwardly rectifying K + current ( I K1 ) as the single mechanistic contributor to the observed immature electrophysiological properties in hESC-CMs. Forced expression of Kir2.1 in hESC-CMs led to robust expression of Ba 2+ -sensitive I K1 and, more importantly, completely ablated all the proarrhythmic action potential traits, rendering the electrophysiological phenotype indistinguishable from the adult counterparts. These results provided the first link of a complex developmentally arrested phenotype to a major effector gene, and importantly, further led us to develop a bio-mimetic culturing strategy for enhancing maturation. Conclusions—: By providing the environmental cues that are missing in conventional culturing method, this approach did not require any genetic or pharmacological interventions. Our findings can facilitate clinical applications, drug discovery, and cardiotoxicity screening by improving the yield, safety, and efficacy of derived CMs.
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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 [13]
The Discussion section, “Mechanisms Underlying the Increased Maturation by Electrical Stimulation” (page unavailable), reports that electrical conditioning promoted several aspects of cardiomyocyte maturation in vitro. It does not establish that cardiac tissue engineering provides a unique cellular niche environment; that part of the claim is unsupported by this paper. (LLM, conf=0.84)
Experimental — accuracy not yet measuredHuman pluripotent stem cells can be differentiated into ventricular cardiomyocytes that prior work has characterized thoroughly at the single-cell level.
“Human pluripotent stem cells (hPSC) can be specified into ventricular cardiomyocytes (vCM) that have been robustly characterized at the single-cell level [2–5].”
From Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells (2018) · cites this paper as [5]
KCNJ2 (KiR2.1) was upregulated in hvCOC by up to about 5-fold.
“Electrophysiologically, KiR2.1 (KCNJ2), which mediates the inwardly rectifying potassium current important for electrical stability of hPSC-CMs [5,29], was upregulated in hvCOC by up to about 5-fold.”
From Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells (2018) · cites this paper as [5]
Experimental — accuracy not yet measured
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- Authors
- Lieu, D. K., Fu, J.-D., Chiamvimonvat, N., Tung, K. C., McNerney, G. P., Huser, T., Keller, G., Kong, C.-W., & Li, R. A.
- Affiliations
- University Health Network (CA)
- From the Cardiovascular Research Center, Mount Sinai School of Medicine, New York, NY (D.K.L., C.-W.K., R.A.L.); the Department of Internal Medicine (D.K.L., N.C.), Department of Cell Biology & Human Anatomy, Division of Cardiovascular Medicine (J.-D.F.), and NSF Center for Biophotonics Science & Technology (G.P.M., T.H.), University of California, Davis, CA; Department of Veterans Affairs, Northern California Health Care System, Mather, CA (N.C.); Stem Cell & Regenerative Medicine...
- Corresponding author
- Li, Ronald A.
- Venue
- Circulation: Arrhythmia and Electrophysiology
- Published
- 2013-02
- Volume
- 6
- Issue
- 1
- Pages
- 191-201
- ISSN
- 1941-3084 (ISSN-L)
- 1941-3149
- PMC
- PMC3757253
- OpenAlex
- W2122723517
- Cited by
- 179
- References
- 46
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 2 · 2023: 10 · 2022: 6 · 2021: 11 · 2020: 14 · 2019: 8 · 2018: 14 · 2017: 28 · 2016: 24 · 2015: 18 · 2014: 16 · 2013: 17
- FWCI
- 11.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Arrhythmia and Electrophysiology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- PUB – Publications at Bielefeld University (Bielefeld University) (submittedVersion)
- Publikationen an der Universität Bielefeld (Universität Bielefeld) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX000576)
- California Institute for Regenerative Medicine
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01 HL85727, R01-HL85844, R01HL085727, R01 HL-72857, R01HL072857, R01HL085844)
- 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
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Keywords
- cardiomyocyte maturation, human embryonic stem cells, induced pluripotent stem cells, Kir2.1, inward rectifier potassium current, drug-induced arrhythmia, action potential, cardiomyocyte differentiation, cardiotoxicity screening, drug discovery
- MeSH terms
- Action Potentials, Arrhythmias, Cardiac, Biological Clocks, Cell Differentiation, Cell Line, Humans, Kinetics, Phenotype, Transfection, Cell Culture Techniques, Potassium Channels, Inwardly Rectifying, Myocytes, Cardiac, Biomimetics, Pluripotent Stem Cells, Embryonic Stem Cells, Induced Pluripotent Stem Cells
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