Extracellular matrix-mediated maturation of human pluripotent stem cell-derived cardiac monolayer structure and electrophysiological function
Open accessAbstract
Background—: Human pluripotent stem cell–derived cardiomyocytes (hPSC-CMs) monolayers generated to date display an immature embryonic-like functional and structural phenotype that limits their utility for research and cardiac regeneration. In particular, the electrophysiological function of hPSC-CM monolayers and bioengineered constructs used to date are characterized by slow electric impulse propagation velocity and immature action potential profiles. Methods and Results—: Here, we have identified an optimal extracellular matrix for significant electrophysiological and structural maturation of hPSC-CM monolayers. hPSC-CM plated in the optimal extracellular matrix combination have impulse propagation velocities ≈2× faster than previously reported (43.6±7.0 cm/s; n=9) and have mature cardiomyocyte action potential profiles, including hyperpolarized diastolic potential and rapid action potential upstroke velocity (146.5±17.7 V/s; n=5 monolayers). In addition, the optimal extracellular matrix promoted hypertrophic growth of cardiomyocytes and the expression of key mature sarcolemmal ( SCN5A , Kir2.1, and connexin43) and myofilament markers (cardiac troponin I). The maturation process reported here relies on activation of integrin signaling pathways: neutralization of β1 integrin receptors via blocking antibodies and pharmacological blockade of focal adhesion kinase activation prevented structural maturation. Conclusions—: Maturation of human stem cell–derived cardiomyocyte monolayers is achieved in a 1-week period by plating cardiomyocytes on PDMS (polydimethylsiloxane) coverslips rather than on conventional 2-dimensional cell culture formats, such as glass coverslips or plastic dishes. Activation of integrin signaling and focal adhesion kinase is essential for significant maturation of human cardiac monolayers.
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Engineered tissues with contractile forces and conduction properties approaching native myocardium have been reported by several groups.
“A number of groups have reported engineered tissues with contractile forces and conduction properties approaching physiologic levels observed in native myocardium [8,13,31,32].”
From Bioengineering an electro-mechanically functional miniature ventricular heart chamber from human pluripotent stem cells (2018) · cites this paper as [32]
The Results (ECM Effects on iCell hiPSC-CM Monolayer Impulse Propagation; page unavailable) report engineered cardiac monolayers with conduction velocities as high as 55 cm/s, approaching the adult-heart range described in the Introduction. The Discussion says their myofilament changes may promote greater tension development, but the paper does not report contractile-force measurements approaching native myocardium. This citation therefore supports the conduction part, not the force part of the sentence. (LLM, conf=0.88)
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References 48 · Cited by 257
Research works printed but not linked: 1
- [24]Zhang J Klos M Wilson GF Herman AM Lian X Raval KK Barron MR Hou L Soerens AG Yu J Palecek SP Lyons GE Thomson JA Herron TJ Jalife J Kamp TJ Extracellular matrix promotes highly efficient cardiac differentiation of human pluripotent stem cells: The matrix sandwich method Circ Res 2012 111 1125 1136 22912385 PMC3482164
- Authors
- Herron, T. J., Rocha, A. M. D., Campbell, K. F., Ponce-Balbuena, D., Willis, B. C., Guerrero-Serna, G., Liu, Q., Klos, M., Musa, H., Zarzoso, M., Bizy, A., Furness, J., Anumonwo, J., Mironov, S., & Jalife, J.
- Affiliations
- Universitat de València (ES)
- From the Center for Arrhythmia Research, Department of Internal Medicine, Cardiovascular Research Center, University of Michigan, Ann Arbor, MI (T.J.H., A.M.D.R., K.C., D.P.-B., B.C.W., G.G.-S., Q.L., J.F., J.A., S.M., J.J.); Department of Medicine, University of California San Diego, La Jolla, CA (M.K.); Davis Heart and Lung Research Institute, Ohio State University, Columbus, OH (H.M.); Shanxi Medical University, Zhejiang, China (Q.L.); and University of Valencia, Valencia, Spain (M.Z., A.B.).
- Venue
- Circulation: Arrhythmia and Electrophysiology
- Published
- 2016-04
- Volume
- 9
- Issue
- 4
- Pages
- e003638-e003638
- ISSN
- 1941-3084 (ISSN-L)
- 1941-3149
- PMC
- PMC4833010
- OpenAlex
- W2337274534
- Cited by
- 257
- References
- 48
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 27 · 2023: 33 · 2022: 35 · 2021: 32 · 2020: 37 · 2019: 31 · 2018: 17 · 2017: 14 · 2016: 6
- FWCI
- 11.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation Arrhythmia and Electrophysiology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL087226, P01HL039707, R01HL122352, R01HL124319)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- human pluripotent stem cell-derived cardiomyocytes, extracellular matrix, cardiomyocyte maturation, electrophysiological maturation, action potential, cardiomyocyte hypertrophy, integrin signaling, focal adhesion kinase, cardiac regeneration, cardiac tissue engineering
- MeSH terms
- Action Potentials, Cell Differentiation, Cell Line, Extracellular Matrix, Humans, Signal Transduction, Myocytes, Cardiac, Electrophysiological Phenomena, Induced Pluripotent Stem Cells
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