Functional sarcoplasmic reticulum for calcium handling of human embryonic stem cell-derived cardiomyocytes: insights for driven maturation
Abstract
Cardiomyocytes (CMs) are nonregenerative. Self-renewable pluripotent human embryonic stem cells (hESCs) can differentiate into CMs for cell-based therapies. In adult CMs, Ca2+-induced Ca2+ release from the sarcoplasmic reticulum (SR) via the ryanodine receptor (RyR) is key in excitation-contraction coupling. Therefore, proper Ca2+ handling properties of hESC-derived CMs are required for their successful functional integration with the recipient heart. Here, we performed a comprehensive analysis of CMs differentiated from the H1 (H1-CMs) and HES2 (HES2-CMs) hESC lines and human fetal (F) and adult (A) left ventricular (LV) CMs. Upon electrical stimulation, all of H1-, HES2-, and FLV-CMs generated similar Ca2+ transients. Caffeine induced Ca2+ release in 65% of FLV-CMs and ∼38% of H1- and HES2-CMs. Ryanodine significantly reduced the electrically evoked Ca2+ transient amplitudes of caffeine-responsive but not -insensitive HES2- and H1-CMs and slowed their upstroke; thapsigargin, which inhibits the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump, reduced the amplitude of only caffeine-responsive HES2- and H1-CMs and slowed the decay. SERCA2a expression was highest in ALV-CMs but comparable among H1-, HES2-, and FLV-CMs. The Na+-Ca2+ exchanger was substantially expressed in both HES2- and H1-CMs relative to FLV- and ALV-CMs. RyR was expressed in HES2-, H1-, and FLV-CMs, but the organized pattern for ALV-CMs was not observed. The regulatory proteins junctin, triadin, and calsequestrin were expressed in ALV-CMs but not HES2- and H1-CMs. We conclude that functional SRs are indeed expressed in hESC-CMs, albeit immaturely. Our results may lead to driven maturation of Ca2+ handling properties of hESC-CMs for enhanced contractile functions. Disclosure of potential conflicts of interest is found at the end of this article.
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Transcript analysis of hvCOC and other engineered constructs showed changes consistent with prior maturation studies.
“Transcript analysis of 2D-cultured clusters [24] and alternative engineered constructs, including human ventricular cardiac micro-tissues (hvCMT; ~1000 cells) [18], tissue strips (hvCTS; ~106 cells) [14] and hvCOC made of identical constituent hPSC-vCMs, revealed changes consistent with our previous maturation studies [18,24–28].”
From Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells (2018) · cites this paper as [25]
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Self-citation
- Authors
- Liu, J., Fu, J. D., Siu, C. W., & Li, R. A.
- Affiliations
- University of California, Davis (US)
- Shriners Hospitals for Children - Northern California (US)
- Corresponding author
- Li, Ronald A.
- Venue
- Stem Cells
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-09-13
- Volume
- 25
- Issue
- 12
- Pages
- 3038-3044
- ISSN
- 1066-5099 (ISSN-L)
- 1549-4918
- OpenAlex
- W1991421066
- Cited by
- 186
- References
- 40
- Citations by year
- 2025: 1 · 2023: 4 · 2022: 1 · 2021: 6 · 2020: 4 · 2019: 8 · 2018: 9 · 2017: 9 · 2016: 17 · 2015: 17 · 2014: 16 · 2013: 19 · 2012: 17
- FWCI
- 4.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Stem Cells (publishedVersion)
- PubMed (publishedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Funders
- California Institute for Regenerative Medicine
- Croucher Foundation
- National Institutes of Health
- University of California, Davis
- National Heart, Lung, and Blood Institute (R01 HL-72857, R01HL072857)
- 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
- sarcoplasmic reticulum, calcium handling, human embryonic stem cell-derived cardiomyocytes, ryanodine receptor, SERCA2a, Na+/Ca2+ exchanger, excitation-contraction coupling, cardiomyocyte maturation, caffeine-induced calcium release, thapsigargin, junctin, triadin, calsequestrin, H1 cell line
- MeSH terms
- Adolescent, Caffeine, Calcium, Cell Differentiation, Cell Line, Fetus, Humans, Ryanodine, Sarcoplasmic Reticulum, Myocytes, Cardiac, Embryonic Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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