ArticleScientific reports2022
p63 silencing induces epigenetic modulation to enhance human cardiac fibroblast to cardiomyocyte-like differentiation.
Article in Scientific reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 14 citations in OpenAlex.
- Integrating delivery systems and microenvironmental cues to accelerate clinical translation of cardiac reprogramming.Materials today. Bio · 2026Review
- Administration of a novel reprogramming formula improves cardiac function and decreases cardiac fibrosis in a myocardial infarction model.JTCVS open · 2025Article
- Cell and tissue reprogramming: Unlocking a new era in medical drug discovery.Pharmacological reviews · 2025Review
- Advances in fibroblast-based cardiac reprogramming in the treatment of heart disease.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2025Review
- Single-cell transcriptomic dynamics of scallop heart reveals the heterogeneous response to heat stress.BMC biology · 2025Article
- Decoding the epigenetic and transcriptional basis of direct cardiac reprogramming.Stem cells (Dayton, Ohio) · 2025Review
- Review
- p63: A Master Regulator at the Crossroads Between Development, Senescence, Aging, and Cancer.Cells · 2025Review
- Review
- Histone deacetylase 6 controls cardiac fibrosis and remodelling through the modulation of TGF-β1/Smad2/3 signalling in post-infarction mice.Journal of cellular and molecular medicine · 2024Article
- Can we stop one heart from breaking: triumphs and challenges in cardiac reprogramming.Current opinion in genetics & development · 2023Review
- Direct Reprogramming of Resident Non-Myocyte Cells and Its Potential for In Vivo Cardiac Regeneration.Cells · 2023Review
- Nkx2.5: a crucial regulator of cardiac development, regeneration and diseases.Frontiers in cardiovascular medicine · 2023Review
- Two decades of heart regeneration research: Cardiomyocyte proliferation and beyond.WIREs mechanisms of diseaseReview
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Direct cell reprogramming represents a promising new myocardial regeneration strategy involving in situ transdifferentiation of cardiac fibroblasts into induced cardiomyocytes. Adult human cells are relatively resistant to reprogramming, however, likely because of epigenetic restraints on reprogramming gene activation. We hypothesized that modulation of the epigenetic regulator gene p63 could improve the efficiency of human cell cardio-differentiation. qRT-PCR analysis demonstrated significantly increased expression of a panel of cardiomyocyte marker genes in neonatal rat and adult rat and human cardiac fibroblasts treated with p63 shRNA (shp63) and the cardio-differentiation factors Hand2/Myocardin (H/M) versus treatment with Gata4, Mef2c and Tbx5 (GMT) with or without shp63 (p < 0.001). FACS analysis demonstrated that shp63+ H/M treatment of human cardiac fibroblasts significantly increased the percentage of cells expressing the cardiomyocyte marker cTnT compared to GMT treatment with or without shp63 (14.8% ± 1.4% versus 4.3% ± 1.1% and 3.1% ± 0.98%, respectively; p < 0.001). We further demonstrated that overexpression of the p63-transactivation inhibitory domain (TID) interferes with the physical interaction of p63 with the epigenetic regulator HDAC1 and that human cardiac fibroblasts treated with p63-TID+ H/M demonstrate increased cardiomyocyte marker gene expression compared to cells treated with shp63+ H/M (p < 0.05). Whereas human cardiac fibroblasts treated with GMT alone failed to contract in co-culture experiments, human cardiac fibroblasts treated with shp63+ HM or p63-TID+ H/M demonstrated calcium transients upon electrical stimulation and contractility synchronous with surrounding neonatal cardiomyocytes. These findings demonstrate that p63 silencing provides enhanced rat and human cardiac fibroblast transdifferentiation into induced cardiomyocytes compared to a standard reprogramming strategy. p63-TID overexpression may be a useful reprogramming strategy for overcoming epigenetic barriers to human fibroblast cardio-differentiation.
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