Neuregulin/ErbB Signaling Regulates Cardiac Subtype Specification in Differentiating Human Embryonic Stem Cells
Open accessAbstract
Rationale: Human embryonic stem cell–derived cardiomyocytes (hESC-CMs) exhibit either a “working” chamber or a nodal-like phenotype. To generate optimal hESC-CM preparations for eventual clinical application in cell-based therapies, we will need to control their differentiation into these specialized cardiac subtypes. Objective: To demonstrate intact neuregulin (NRG)-1β/ErbB signaling in hESC-CMs and test the hypothesis that this signaling pathway regulates cardiac subtype abundance in hESC-CM cultures. Methods and Results: All experiments used hESC-CM cultures generated using our recently reported directed differentiation protocol. To support subsequent action potential phenotyping approaches and provide a higher-throughput method of determining cardiac subtype, we first developed and validated a novel genetic label that identifies nodal-type hESC-CMs. Next, control hESC-CM preparations were compared to those differentiated in the presence of exogenous NRG-1β, an anti–NRG-1β neutralizing antibody, or the ErbB antagonist AG1478. We used 3 independent approaches to determine the ratio of cardiac subtypes in the resultant populations: direct action potential phenotyping under current-clamp, activation of the aforementioned genetic label, and subtype-specific marker expression by RT-PCR. Using all 3 end points, we found that inhibition of NRG-1β/ErbB signaling greatly enhanced the proportion of cells showing the nodal phenotype. Conclusions: NRG-1β/ErbB signaling regulates the ratio of nodal- to working-type cells in differentiating hESC-CM cultures and presumably functions similarly during early human heart development. We speculate that, by manipulating NRG-1β/ErbB signaling, it will be possible to generate preparations of enriched working-type myocytes for infarct repair, or, conversely, nodal cells for potential use in a biological pacemaker.
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Although some protocols have reported differentiation of ventricular, atrial, and pacemaker cardiomyocyte subtypes, they still require standardization and harmonization because they produce heterogeneous cell populations.
“Although few protocols reported differentiation of different subtypes of CMs including the ventricular [399,400], atrial [401,402], and pacemaker cells [172,398,403], they still need standardization and harmonization as they result in heterogeneous cell populations.”
From Cardiovascular disease models: A game changing paradigm in drug discovery and screening (2019) · cites this paper as [172]
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- Authors
- Zhu, W.-Z., Xie, Y., Moyes, K. W., Gold, J. D., Askari, B., & Laflamme, M. A.
- Affiliations
- From the Center for Cardiovascular Biology, Department of Pathology (W.-Z.Z., Y.X., K.W.M., B.A., M.A.L.) and Institute for Stem Cell and Regenerative Medicine (W.-Z.Z., Y.X., K.W.M., M.A.L.), University of Washington, Seattle; and Geron Corporation (J.D.G.), Menlo Park, Calif.
- University of Washington (US)
- Venue
- Circulation Research
- Published
- 2010-09-17
- Volume
- 107
- Issue
- 6
- Pages
- 776-786
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- PMC
- PMC2941561
- OpenAlex
- W2108892010
- Cited by
- 228
- References
- 90
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 5 · 2023: 4 · 2022: 10 · 2021: 17 · 2020: 19 · 2019: 5 · 2018: 10 · 2017: 24 · 2016: 20 · 2015: 17 · 2014: 21 · 2013: 21 · 2012: 28
- FWCI
- 9.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Eli Lilly and Company
- National Institutes of Health (5r01hl064387-10)
- National Heart, Lung, and Blood Institute (R01-HL064387, K08HL080431, P01HL094374, K08-HL80431)
- 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 › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- neuregulin-1β, ErbB signaling, human embryonic stem cell-derived cardiomyocytes, AG1478, biological pacemaker, heart development
- MeSH terms
- Animals, Cell Differentiation, Cell Line, Cells, Cultured, Humans, Sinoatrial Node, Signal Transduction, Neuregulin-1, Myocytes, Cardiac, Mice, Embryonic Stem Cells, ErbB Receptors
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