Evidence map›Paper›PMID 26675706›Full record

ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2016

Time-dependent evolution of functional vs. remodeling signaling in induced pluripotent stem cell-derived cardiomyocytes and induced maturation with biomechanical stimulation.

Gwanghyun Jung, Giovanni Fajardo, Alexandre J S Ribeiro, Kristina Bezold Kooiker, Michael Coronado, Mingming Zhao, Dong-Qing Hu, Sushma Reddy, Kazuki Kodo, Krishna Sriram and 4 more

Abstract read
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In one paragraph

Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 46 papers.

0numbers the graph read from it
0cells of the map it votes in
46citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

46 citing papers in PubMed.

  1. Beta-Adrenergic Stimulation andbioRxiv : the preprint server for biology · 2026
    Article
  2. Article
  3. Genomics of pediatric cardiomyopathy.Pediatric research · 2025
    Review
  4. Article
  5. Review
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  7. hiPSC-CM electrophysiology: impact of temporal changes and study parameters on experimental reproducibility.American journal of physiology. Heart and circulatory physiology · 2024
    Article
  8. Article
  9. Review
  10. Article
  11. Article
  12. Article
  13. Article
  14. Review
  15. Article
  16. Review
  17. Hypertrophic cardiomyopathy β-cardiac myosin mutation (P710R) leads to hypercontractility by disrupting super relaxed state.Proceedings of the National Academy of Sciences of the United States of America · 2021
    Article
  18. Human iPSC-engineered cardiac tissue platform faithfully models important cardiac physiology.American journal of physiology. Heart and circulatory physiology · 2021
    Article
  19. Review
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Gwanghyun Jung*Division of Cardiology, Department of Pediatrics, Stanford Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Mechanical Engineering, Stanford University School of Engineering, Stanford, California, USA; and Departments of Pharmacology and Medicine, University of California, San Diego, San Diego, California, USA.
Giovanni Fajardo*Division of Cardiology, Department of Pediatrics, Stanford Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Mechanical Engineering, Stanford University School of Engineering, Stanford, California, USA; and Departments of Pharmacology and Medicine, University of California, San Diego, San Diego, California, USA.
Alexandre J S Ribeiro*Division of Cardiology, Department of Pediatrics, Stanford Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Mechanical Engineering, Stanford University School of Engineering, Stanford, California, USA; and Departments of Pharmacology and Medicine, University of California, San Diego, San Diego, California, USA.
Kristina Bezold Kooiker*Division of Cardiology, Department of Pediatrics, Stanford Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Mechanical Engineering, Stanford University School of Engineering, Stanford, California, USA; and Departments of Pharmacology and Medicine, University of California, San Diego, San Diego, California, USA.
Michael Coronado*Division of Cardiology, Department of Pediatrics, Stanford Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Mechanical Engineering, Stanford University School of Engineering, Stanford, California, USA; and Departments of Pharmacology and Medicine, University of California, San Diego, San Diego, California, USA.
Mingming Zhao*Division of Cardiology, Department of Pediatrics, Stanford Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Mechanical Engineering, Stanford University School of Engineering, Stanford, California, USA; and Departments of Pharmacology and Medicine, University of California, San Diego, San Diego, California, USA.
Dong-Qing Hu*Division of Cardiology, Department of Pediatrics, Stanford Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Mechanical Engineering, Stanford University School of Engineering, Stanford, California, USA; and Departments of Pharmacology and Medicine, University of California, San Diego, San Diego, California, USA.
Sushma Reddy*Division of Cardiology, Department of Pediatrics, Stanford Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Mechanical Engineering, Stanford University School of Engineering, Stanford, California, USA; and Departments of Pharmacology and Medicine, University of California, San Diego, San Diego, California, USA.
Kazuki Kodo*Division of Cardiology, Department of Pediatrics, Stanford Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Mechanical Engineering, Stanford University School of Engineering, Stanford, California, USA; and Departments of Pharmacology and Medicine, University of California, San Diego, San Diego, California, USA.
Krishna Sriram*Division of Cardiology, Department of Pediatrics, Stanford Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Mechanical Engineering, Stanford University School of Engineering, Stanford, California, USA; and Departments of Pharmacology and Medicine, University of California, San Diego, San Diego, California, USA.
Paul A Insel*Division of Cardiology, Department of Pediatrics, Stanford Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Mechanical Engineering, Stanford University School of Engineering, Stanford, California, USA; and Departments of Pharmacology and Medicine, University of California, San Diego, San Diego, California, USA.
Joseph C Wu*Division of Cardiology, Department of Pediatrics, Stanford Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Mechanical Engineering, Stanford University School of Engineering, Stanford, California, USA; and Departments of Pharmacology and Medicine, University of California, San Diego, San Diego, California, USA.
Beth L Pruitt*Division of Cardiology, Department of Pediatrics, Stanford Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Mechanical Engineering, Stanford University School of Engineering, Stanford, California, USA; and Departments of Pharmacology and Medicine, University of California, San Diego, San Diego, California, USA.
Daniel Bernstein*Division of Cardiology, Department of Pediatrics, Stanford Cardiovascular Institute, Division of Cardiovascular Medicine, Department of Medicine, and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA; Department of Mechanical Engineering, Stanford University School of Engineering, Stanford, California, USA; and Departments of Pharmacology and Medicine, University of California, San Diego, San Diego, California, USA danb@stanford.edu.

Funding

Training in Myocardial Biology at Stanford (TIMBS)T32HL094274 · NHLBI · STANFORD UNIVERSITY · PI Euan A Ashley, Daniel Bernstein · 2010 to 2026
$5.0M
hiPSC-Cardiomyocytes to Screen Variants Predictive of Doxorubicin CardiotoxicityR33HL123655 · NHLBI · STANFORD UNIVERSITY · PI BERNSTEIN, DANIEL · 2016 to 2018
$1.4M
hiPSC-Cardiomyocytes to Screen Variants Predictive of Doxorubicin CardiotoxicityR21HL123655 · NHLBI · STANFORD UNIVERSITY · PI BERNSTEIN, DANIEL · 2014 to 2015
$434k
B-adrenergic receptor (B-AR) signaling pathways in human induced pluripotent stem cell-derived cardiomyocytes, hiPSC-CMsF32HL126348 · NHLBI · STANFORD UNIVERSITY · PI JUNG, GWANGHYUN · 2015 to 2017
$184k
NHLBI NIH HHS F32 HL126348NHLBI NIH HHS F32HL126348NHLBI NIH HHS HL11300604NHLBI NIH HHS HL11708301NHLBI NIH HHS HL123655NHLBI NIH HHS R21 HL123655NHLBI NIH HHS R33 HL123655NHLBI NIH HHS T32 HL094274
6 · The paper itself

Abstract

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a powerful platform for uncovering disease mechanisms and assessing drugs for efficacy/toxicity. However, the accuracy with which hiPSC-CMs recapitulate the contractile and remodeling signaling of adult cardiomyocytes is not fully known. We used β-adrenergic receptor (β-AR) signaling as a prototype to determine the evolution of signaling component expression and function during hiPSC-CM maturation. In "early" hiPSC-CMs (less than or equal to d 30), β2-ARs are a primary source of cAMP/PKA signaling. With longer culture, β1-AR signaling increases: from 0% of cAMP generation at d 30 to 56.8 ± 6.6% by d 60. PKA signaling shows a similar increase: 15.7 ± 5.2% (d 30), 49.8 ± 0.5% (d 60), and 71.0 ± 6.1% (d 90). cAMP generation increases 9-fold from d 30 to 60, with enhanced coupling to remodeling pathways (e.g., Akt and Ca(2+)/calmodulin-dependent protein kinase type II) and development of caveolin-mediated signaling compartmentalization. By contrast, cardiotoxicity induced by chronic β-AR stimulation, a major component of heart failure, develops much later: 5% cell death at d 30vs 55% at d 90. Moreover, β-AR maturation can be accelerated by biomechanical stimulation. The differential maturation of β-AR functionalvs remodeling signaling in hiPSC-CMs has important implications for their use in disease modeling and drug testing. We propose that assessment of signaling be added to the indices of phenotypic maturation of hiPSC-CMs.-Jung, G., Fajardo, G., Ribeiro, A. J. S., Kooiker, K. B., Coronado, M., Zhao, M., Hu, D.-Q., Reddy, S., Kodo, K., Sriram, K., Insel, P. A., Wu, J. C., Pruitt, B. L., Bernstein, D. Time-dependent evolution of functionalvs remodeling signaling in induced pluripotent stem cell-derived cardiomyocytes and induced maturation with biomechanical stimulation.

Indexed as

Biomechanical PhenomenaCalciumCell DifferentiationCells, CulturedCyclic AMPGene Expression ProfilingHEK293 CellsHumansImmunoblottingInduced Pluripotent Stem CellsMicroscopy, ConfocalMyocytes, CardiacOligonucleotide Array Sequence AnalysisReceptors, Adrenergic, beta-1Receptors, Adrenergic, beta-2Reverse Transcriptase Polymerase Chain ReactionCalciumCyclic AMPReceptors, Adrenergic, beta-1Receptors, Adrenergic, beta-2cardiotoxicity testingcell signaling maturationβ-adrenergic receptor

Identifiers

PMID26675706
PMCPMC4799510

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.