Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18
Open accessAbstract
The heartbeat originates within the sinoatrial node (SAN), a small structure containing <10,000 genuine pacemaker cells. If the SAN fails, the ∼5 billion working cardiomyocytes downstream of it become quiescent, leading to circulatory collapse in the absence of electronic pacemaker therapy. Here we demonstrate conversion of rodent cardiomyocytes to SAN cells in vitro and in vivo by expression of Tbx18, a gene critical for early SAN specification. Within days of in vivo Tbx18 transduction, 9.2% of transduced, ventricular cardiomyocytes develop spontaneous electrical firing physiologically indistinguishable from that of SAN cells, along with morphological and epigenetic features characteristic of SAN cells. In vivo, focal Tbx18 gene transfer in the guinea-pig ventricle yields ectopic pacemaker activity, correcting a bradycardic disease phenotype. Myocytes transduced in vivo acquire the cardinal tapering morphology and physiological automaticity of native SAN pacemaker cells. The creation of induced SAN pacemaker (iSAN) cells opens new prospects for bioengineered pacemakers.
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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 [403]
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- Authors
- Kapoor, N., Liang, W., Marbán, E., & Cho, H. C.
- Affiliations
- Cedars-Sinai Medical Center (US)
- Corresponding author
- Marbán, Eduardo
- Cho, Hee Cheol
- Venue
- Nature Biotechnology
- Published
- 2012-12-16
- Volume
- 31
- Issue
- 1
- Pages
- 54-62
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC3775583
- OpenAlex
- W2088386461
- Cited by
- 321
- References
- 56
- Citations by year
- 2026: 16 · 2025: 13 · 2024: 13 · 2023: 16 · 2022: 29 · 2021: 22 · 2020: 25 · 2019: 30 · 2018: 30 · 2017: 25 · 2016: 23 · 2015: 36 · 2014: 29 · 2013: 13
- FWCI
- 10.02
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- American Heart Association
- Heart and Stroke Foundation of Canada
- Heart Rhythm Society
- National Heart, Lung, and Blood Institute (R01HL111646)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- Tbx18, sinoatrial node, pacemaker cells, cellular reprogramming, automaticity, bradycardia, gene therapy, ventricular myocytes, spontaneous electrical activity
- MeSH terms
- Animals, Animals, Newborn, Calcium, Cell Differentiation, Cells, Cultured, Myocardium, Sinoatrial Node, T-Box Domain Proteins, Rats
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