Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy
Open accessAbstract
Lamin A/C (LMNA) is one of the most frequently mutated genes associated with dilated cardiomyopathy (DCM). DCM related to mutations in LMNA is a common inherited cardiomyopathy that is associated with systolic dysfunction and cardiac arrhythmias. Here we modelled the LMNA-related DCM in vitro using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Electrophysiological studies showed that the mutant iPSC-CMs displayed aberrant calcium homeostasis that led to arrhythmias at the single-cell level. Mechanistically, we show that the platelet-derived growth factor (PDGF) signalling pathway is activated in mutant iPSC-CMs compared to isogenic control iPSC-CMs. Conversely, pharmacological and molecular inhibition of the PDGF signalling pathway ameliorated the arrhythmic phenotypes of mutant iPSC-CMs in vitro. Taken together, our findings suggest that the activation of the PDGF pathway contributes to the pathogenesis of LMNA-related DCM and point to PDGF receptor-β (PDGFRB) as a potential therapeutic target.
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Human iPSC differentiation into cardiomyocytes using an established small-molecule Wnt-activation/inhibition protocol yields 95% pure TNNT2+ cardiomyocytes.
“Human iPSC differentiation into CM was performed on three individual donor lines using an established small-molecule Wnt-activation/inhibition protocol yielding 95% pure TNNT2+ CM (Burridge et al., 2014; Lee et al., 2019; Kitani et al., 2019).”
From Splice-Junction-Based Mapping of Alternative Isoforms in the Human Proteome (2019) · cites this paper as Lee et al., 2019
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References 45 · Cited by 222
Research works printed but not linked: 1
- [4]Hershberger RE & Morales A LMNA-Related Dilated Cardiomyopathy in GeneReviews(®) (eds. Pagon RA) (University of Washington, Seattle, 1993). 20301717
- Authors
- Lee, J., Termglinchan, V., Diecke, S., Itzhaki, I., Lam, C. K., Garg, P., Lau, E., Greenhaw, M., Seeger, T., Wu, H., Zhang, J. Z., Chen, X., Gil, I. P., Ameen, M., Sallam, K., Rhee, J.-W., Churko, J. M., Chaudhary, R., Chour, T., Wang, P. J., Snyder, M. P., Chang, H. Y., Karakikes, I., & Wu, J. C.
- Affiliations
- Stanford Medicine (US)
- Max Delbrück Center (DE)
- Stanford University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Lee, Jaecheol
- Karakikes, Ioannis
- Wu, Joseph C.
- ORCID
- Venue
- Nature
- Published
- 2019-07-17
- Volume
- 572
- Issue
- 7769
- Pages
- 335-340
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC6779479
- OpenAlex
- W2958723445
- Cited by
- 222
- References
- 45
- Citations by year
- 2026: 21 · 2025: 29 · 2024: 41 · 2023: 29 · 2022: 34 · 2021: 38 · 2020: 20 · 2019: 10
- FWCI
- 18.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- American Heart Association (17IRG33410532)
- National Heart, Lung, and Blood Institute (K99HL133473, R00HL133473, F32HL139045, R00HL104002, R01HL132875, R01HL128170, R24HL117756, R01HL139679, R01HL113006, R01HL141851, R01HL130020, T32HL094274)
- National Human Genome Research Institute (RM1HG007735, P50HG007735)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- LMNA mutations, dilated cardiomyopathy, lamin A/C, PDGFRβ, iPSC-derived cardiomyocytes, calcium homeostasis, cardiac arrhythmias, familial cardiomyopathy, therapeutic target
- MeSH terms
- Arrhythmias, Cardiac, Calcium, Cardiomyopathy, Dilated, Cells, Cultured, Chromatin, Homeostasis, Humans, Models, Biological, Mutation, Platelet-Derived Growth Factor, RNA, Messenger, Signal Transduction, Receptor, Platelet-Derived Growth Factor beta, Myocytes, Cardiac, Lamin Type A, Chromatin Assembly and Disassembly, Induced Pluripotent Stem Cells, Haploinsufficiency, Single-Cell Analysis, Nonsense Mediated mRNA Decay, In Vitro Techniques
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