ArticleCell stem cell2020
Wnt Activation and Reduced Cell-Cell Contact Synergistically Induce Massive Expansion of Functional Human iPSC-Derived Cardiomyocytes.
Open access · bronzeAbstract read
In one paragraph
Article in Cell stem cell, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 132 papers, 2 of them syntheses that pooled it.
0numbers the graph read from it
0cells of the map it votes in
132citing papers in PubMed, 2 pooled it
9.8field-weighted citation impact, top 1% of its field
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.
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.
Who cites it
132 citing papers in PubMed, 2 syntheses or guidelines pooled it, 225 citations in OpenAlex.
- Advances and Prospects in Using Induced Pluripotent Stem Cells for 3D Bioprinting in Cardiac Tissue Engineering.Reviews in cardiovascular medicine · 2025Pooled it
- Using human induced pluripotent stem cell-derived cardiomyocytes to understand the mechanisms driving cardiomyocyte maturation.Frontiers in cardiovascular medicine · 2022Pooled it
- A bifunctional actuator to correct loss-of-function deficits in cardiac voltage-gated sodium channels.Science advances · 2026Article
- Micro- and Macro-Heterogeneity of N-Glycoproteome Remodeling in Endoplasmic Reticulum Stress.Molecular & cellular proteomics : MCP · 2026Article
- Heart-on-a-chip and vasculature-on-a-chip platforms as models of cardiovascular disease.Nature reviews. Cardiology · 2026Review
- CALIPERS: Cell cycle-aware live imaging for phenotyping experiments and regeneration studies.Nature communications · 2026Article
- Signaling pathways regulating cardiac regeneration.Cell regeneration (London, England) · 2026Review
- Machine learning-guided risk stratification for long QT syndrome genetic variants with hiPSC-derived cardiomyocytes.Cardiovascular research · 2026Article
- Protocol for insulin dosing during expansion and maturation of human iPSC-derived cardiomyocytes.STAR protocols · 2026Article
- Senescence modulated cardiac repair with pluripotent stem cell-derived cardiomyocytes.Stem cell research & therapy · 2026Article
- Sustained β-catenin activation via GSK3 inhibition promotes direct fibroblast-to-cardiomyocyte reprogramming.The Journal of biological chemistry · 2026Article
- Extracellular Vesicles Released by Picornavirus-Infected Cells Modify Antiviral Immune Cell Responses.Journal of extracellular vesicles · 2026Article
- Disease modelling with in vitro vascularised organoids.Disease models & mechanisms · 2026Review
- An organic artificial cardiomyocyte.Nature communications · 2026Article
- Beyond Transconductance: Cell-Polymer Coupling Determines Fidelity in Action Potential Recording via Electrolyte-Gated Polymer Transistors.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Mechanisms and Therapeutic Potential of Human Cardiomyocyte Proliferation.Journal of cardiovascular development and disease · 2026Review
- Paligenosis: dual potential of mature cell plasticity in regeneration and tumorigenesis.MedScience · 2026Review
- Recent advances and challenges in hydrogel-based delivery of immunomodulatory strategies for diabetic wound healing.Theranostics · 2026Review
- YAP1 reactivation in cardiomyocytes following ECM remodelling contributes to the development of contractile force and sarcomere maturation.Cell death discovery · 2025Article
- A gene regulatory element modulates myosin expression and controls cardiomyocyte response to stress.Genome research · 2025Article
72 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
37 authors at 8 institutions in 3 countries.
Jan W BuikemaCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Utrecht Regenerative Medicine Center, Circulatory Health Laboratory, University Utrecht, Department of Cardiology, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands.
Soah LeeCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
William R GoodyerCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Pediatric Cardiology, Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA.
Renee G MaasUtrecht Regenerative Medicine Center, Circulatory Health Laboratory, University Utrecht, Department of Cardiology, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands.
Orlando ChirikianCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Guang LiCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Yi MiaoDepartment of Molecular and Cellular Physiology, Howard Hughes Medical Institute, and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Sharon L PaigeCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Pediatric Cardiology, Department of Pediatrics, Stanford School of Medicine, Stanford, CA 94305, USA.
Daniel LeeCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Haodi WuCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
David T PaikCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Siyeon RheeDepartment of Biology, Stanford University, Stanford, CA 94305, USA.
Lei TianCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Francisco X GaldosCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Nazan PulucaCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Benjamin BeyersdorfCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
James HuCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Aimee BeckCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Sneha VenkamatranCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
Srilatha SwamiDivision of Endocrinology and Metabolism, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Paul WijnkerAmsterdam Cardiovascular Sciences, Department of Physiology, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
Maike SchuldtAmsterdam Cardiovascular Sciences, Department of Physiology, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
Larissa M DorschAmsterdam Cardiovascular Sciences, Department of Physiology, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
Alain van MilUtrecht Regenerative Medicine Center, Circulatory Health Laboratory, University Utrecht, Department of Cardiology, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands.
Kristy Red-HorseCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biology, Stanford University, Stanford, CA 94305, USA.
Joy Y WuDivision of Endocrinology and Metabolism, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Caroline GeisenInstitute of Physiology I, Life and Brain Center, Medical Faculty, University of Bonn, 53105 Bonn, Germany.
Michael HesseInstitute of Physiology I, Life and Brain Center, Medical Faculty, University of Bonn, 53105 Bonn, Germany.
Vahid SerpooshanCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biomedical Engineering, Emory University and Georgia Institute of Technology, Atlanta, GA 30322, USA.
Stefan JovingeDeVos Cardiovascular Research Program of Spectrum Health and Van Andel Research Institute, 100 Michigan Street NE, Grand Rapids, MI 49503, USA; Michigan State University, College of Human Medicine, 15 Michigan Street NE, Grand Rapids, MI, USA.
Bernd K FleischmannInstitute of Physiology I, Life and Brain Center, Medical Faculty, University of Bonn, 53105 Bonn, Germany.
Pieter A DoevendansUtrecht Regenerative Medicine Center, Circulatory Health Laboratory, University Utrecht, Department of Cardiology, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands; Netherlands Heart Institute, Holland Heart House, 3511 EP Utrecht, the Netherlands.
Jolanda van der VeldenAmsterdam Cardiovascular Sciences, Department of Physiology, Amsterdam University Medical Centers, Amsterdam, the Netherlands.
K Christopher GarciaDepartment of Molecular and Cellular Physiology, Howard Hughes Medical Institute, and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Joseph C WuCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Radiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Joost P G SluijterUtrecht Regenerative Medicine Center, Circulatory Health Laboratory, University Utrecht, Department of Cardiology, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands.
Sean M WuCardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: smwu@stanford.edu.
Stanford University · USCardiovascular Institute of the South · USAmsterdam University Medical Centers · NLUniversity Medical Center Utrecht · NLLife & Brain (Germany) · DEStanford Medicine · USUniversity of Bonn · DEVan Andel Institute · US
Funding
Project 3 (Mercola)P01HL141084 · NHLBI · STANFORD UNIVERSITY · PI Joseph C. Wu · 2019 to 2026
$21.1MFrom proteins to cells to tissues: A multi-scale assessment of biomechanical regulation by the myosin molecular motorRM1GM131981 · NIGMS · STANFORD UNIVERSITY · PI BERNSTEIN, DANIEL, MACK, DAVID LEE · 2019 to 2023
$10.3MInduced pluripotent stem cells in the understanding and treatment of heart diseaseU01HL099776 · NHLBI · STANFORD UNIVERSITY · PI LONGAKER, MICHAEL T, WU, JOSEPH C. · 2009 to 2015
$8.2MSingle Cell Sequencing of Human iPSC-CM Subtype Identity and FunctionR01HL145676 · NHLBI · STANFORD UNIVERSITY · PI MARK MERCOLA, Joseph C. Wu · 2019 to 2026
$5.1MHuman iPSC Model to Elucidate Metabolic Interplay in Diabetic CardimyopathyR01HL146690 · NHLBI · STANFORD UNIVERSITY · PI LIAO, RONGLIH, MERCOLA, MARK · 2019 to 2025
$5.1MEnabling Technologies for Human-Machine Hybrid TissuesDP1LM012179 · NLM · STANFORD UNIVERSITY · PI WU, SEAN M · 2014 to 2018
$3.8MGeneration of functional organs via developmental chimerismDP2OD004411 · OD · STANFORD UNIVERSITY · PI WU, SEAN M · 2008 to 2008
$2.5MCellular and Molecular Mechanisms of Atrial Cardiomyocyte Lineage Commitment R00HL133472 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI LI, GUANG · 2019 to 2021
$750kHigh Throughput DNA Sequencer UpgradeS10OD018220 · OD · STANFORD UNIVERSITY · PI COLLER, JOHN · 2014 to 2014
$596kIdentifying Angiocrine Factors for Cardiomyocyte Maturation Using Single-Cell SequencingK99HL150216 · NHLBI · STANFORD UNIVERSITY · PI PAIK, DAVID T · 2020 to 2021
$325kMolecular and Cellular Mechanisms of Neonatal Cardiac Development and RepairK99HL127295 · NHLBI · STANFORD UNIVERSITY · PI SERPOOSHAN, VAHID · 2016 to 2017
$238kPatient-Specific Induced Pluripotent Stem Cells for Modeling Single Ventricle Congenital Heart DiseaseK08HL148553 · NHLBI · STANFORD UNIVERSITY · PI PAIGE, SHARON LYNN · 2019 to 2020
$212kNHLBI NIH HHS F30 HL149152NHLBI NIH HHS F32 HL142205NHLBI NIH HHS K08 HL148553NHLBI NIH HHS K99 HL127295NHLBI NIH HHS K99 HL150216NHLBI NIH HHS P01 HL141084NHLBI NIH HHS R00 HL133472NHLBI NIH HHS R01 HL145676NHLBI NIH HHS R01 HL146690NHLBI NIH HHS U01 HL099776NIGMS NIH HHS RM1 GM131981NIH HHS DP2 OD004411NIH HHS S10 OD018220NLM NIH HHS DP1 LM012179
Abstract
Modulating signaling pathways including Wnt and Hippo can induce cardiomyocyte proliferation in vivo. Applying these signaling modulators to human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in vitro can expand CMs modestly (<5-fold). Here, we demonstrate massive expansion of hiPSC-CMs in vitro (i.e., 100- to 250-fold) by glycogen synthase kinase-3β (GSK-3β) inhibition using CHIR99021 and concurrent removal of cell-cell contact. We show that GSK-3β inhibition suppresses CM maturation, while contact removal prevents CMs from cell cycle exit. Remarkably, contact removal enabled 10 to 25 times greater expansion beyond GSK-3β inhibition alone. Mechanistically, persistent CM proliferation required both LEF/TCF activity and AKT phosphorylation but was independent from yes-associated protein (YAP) signaling. Engineered heart tissues from expanded hiPSC-CMs showed comparable contractility to those from unexpanded hiPSC-CMs, demonstrating uncompromised cellular functionality after expansion. In summary, we uncovered a molecular interplay that enables massive hiPSC-CM expansion for large-scale drug screening and tissue engineering applications.
Indexed as
Induced Pluripotent Stem CellsCell DifferentiationCells, CulturedGlycogen Synthase Kinase 3 betaHumansMyocytes, CardiacGlycogen Synthase Kinase 3 betacardiomyocytesexpansionGSK3induced pluripotent stem cellsmaturationproliferationWnt signaling
Identifiers
What OpenQuestion holds
Textmetadata
LicenceTDM
Read underepoch 390
Registered trials
None linked
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.