Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions
Open accessAbstract
The protocol described here efficiently directs human pluripotent stem cells (hPSCs) to functional cardiomyocytes in a completely defined, growth factor- and serum-free system by temporal modulation of regulators of canonical Wnt signaling. Appropriate temporal application of a glycogen synthase kinase 3 (GSK3) inhibitor combined with the expression of β-catenin shRNA or a chemical Wnt inhibitor is sufficient to produce a high yield (0.8-1.3 million cardiomyocytes per cm(2)) of virtually pure (80-98%) functional cardiomyocytes in 14 d from multiple hPSC lines without cell sorting or selection. Qualitative (immunostaining) and quantitative (flow cytometry) characterization of differentiated cells is described to assess the expression of cardiac transcription factors and myofilament proteins. Flow cytometry of BrdU incorporation or Ki67 expression in conjunction with cardiac sarcomere myosin protein expression can be used to determine the proliferative capacity of hPSC-derived cardiomyocytes. Functional human cardiomyocytes differentiated via these protocols may constitute a potential cell source for heart disease modeling, drug screening and cell-based therapeutic applications.
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hiPSC-CM differentiation was conducted for 15 days following published protocols.
“The differentiation process for hiPSC-CMs was conducted for 15 days following published protocols52.”
From Fibre-infused gel scaffolds guide cardiomyocyte alignment in 3D-printed ventricles (2023) · cites this paper as [52]
Cardiomyocytes can reliably be derived from human embryonic stem cells and induced pluripotent stem cells using protocols with timed growth factors or small molecules designed to recapitulate developmental pathways.
“CMs can reliably be derived from human embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) using protocols that involve timed application of GFs or small molecules, that are designed to recapitulate developmental pathways.”
From Cardiovascular disease models: A game changing paradigm in drug discovery and screening (2019) · cites this paper as [150]
Optimal cardiogenic mesoderm induction for all hESC and hiPSC lines was found at 1-4 μM CHIR99021 concentrations, rather than the typical 10-12 μM range reported for monolayer methods.
“Optimal cardiogenic mesoderm induction for all human embryonic stem cell (hESC) and induced pluripotent stem cell (hiPSC) lines was found at 1–4 μM CHIR99021 concentrations, rather than the typical 10–12 µM range reported for monolayer methods14,21–27.”
From Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease (2021) · cites this paper as [21]
BMP4 and Activin A have been used successfully for cardiomyocyte differentiation.
“successful cardiomyocyte differentiation has been achieved in the past using morphogens such as BMP4 and Activin A21,26.”
From Self-assembling human heart organoids for the modeling of cardiac development and congenital heart disease (2021) · cites this paper as [21]
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- Authors
- Lian, X., Zhang, J., Azarin, S. M., Zhu, K., Hazeltine, L. B., Bao, X., Hsiao, C., Kamp, T. J., & Palecek, S. P.
- Affiliations
- University of Wisconsin–Madison (US)
- Corresponding author
- Palecek, Sean P
- ORCID
- Venue
- Nature Protocols
- Published
- 2012-12-20
- Volume
- 8
- Issue
- 1
- Pages
- 162-175
- ISSN
- 1750-2799 (ISSN-L)
- 1754-2189
- PMC
- PMC3612968
- OpenAlex
- W2083599207
- Cited by
- 1,748
- References
- 24
- Citations by year
- 2026: 115 · 2025: 160 · 2024: 188 · 2023: 158 · 2022: 168 · 2021: 176 · 2020: 183 · 2019: 125 · 2018: 101 · 2017: 119 · 2016: 101 · 2015: 85 · 2014: 48 · 2013: 21
- FWCI
- 19.78
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Protocols (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (U01HL099773)
- National Cancer Institute (P30CA014520)
- National Institute of Biomedical Imaging and Bioengineering (R01EB007534)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- cardiomyocyte differentiation, human pluripotent stem cells, Wnt/β-catenin signaling, glycogen synthase kinase-3 inhibition, serum-free differentiation, cardiomyocyte proliferation, cardiac myosin, drug screening, cell therapy
- MeSH terms
- Cell Differentiation, Flow Cytometry, Humans, Lentivirus, Cell Culture Techniques, Myocytes, Cardiac, RNA, Small Interfering, Pluripotent Stem Cells, beta Catenin, Wnt Signaling Pathway
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