ArticleStem cell research & therapy2021
GATA-targeted compounds modulate cardiac subtype cell differentiation in dual reporter stem cell line.
Article in Stem cell research & therapy, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 18 citations in OpenAlex.
- Cardiac drug potential: exploring individual and combined cardiac drugs to promote differentiation of adipose-derived stem cells into cardiomyocytes.Molecular biology reports · 2026Article
- GATA4-targeted compounds induce apoptosis and diminish viability of hepatoblastoma cells.PloS one · 2026Article
- A biodegradable, microstructured, electroconductive and nano-integrated drug eluting patch (MENDEP) for myocardial tissue engineering.Bioactive materials · 2025Article
- The role of GATA4 in mesenchymal stem cell senescence: A new frontier in regenerative medicine.Regenerative therapy · 2025Review
- Decoding congenital heart disease: a multi-omic framework for cardiac lineage and regulatory dysfunction.Frontiers in cell and developmental biology · 2025Review
- Recent Insights into Endogenous Mammalian Cardiac Regeneration Post-Myocardial Infarction.International journal of molecular sciences · 2024Review
- Switching of hypertrophic signalling towards enhanced cardiomyocyte identity and maturity by a GATA4-targeted compound.Stem cell research & therapy · 2024Article
- Nkx2.5: a crucial regulator of cardiac development, regeneration and diseases.Frontiers in cardiovascular medicine · 2023Review
- Cardiac stem cells: Current knowledge and future prospects.World journal of stem cells · 2022Review
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundPharmacological modulation of cell fate decisions and developmental gene regulatory networks holds promise for the treatment of heart failure. Compounds that target tissue-specific transcription factors could overcome non-specific effects of small molecules and lead to the regeneration of heart muscle following myocardial infarction. Due to cellular heterogeneity in the heart, the activation of gene programs representing specific atrial and ventricular cardiomyocyte subtypes would be highly desirable. Chemical compounds that modulate atrial and ventricular cell fate could be used to improve subtype-specific differentiation of endogenous or exogenously delivered progenitor cells in order to promote cardiac regeneration.
methodsTranscription factor GATA4-targeted compounds that have previously shown in vivo efficacy in cardiac injury models were tested for stage-specific activation of atrial and ventricular reporter genes in differentiating pluripotent stem cells using a dual reporter assay. Chemically induced gene expression changes were characterized by qRT-PCR, global run-on sequencing (GRO-seq) and immunoblotting, and the network of cooperative proteins of GATA4 and NKX2-5 were further explored by the examination of the GATA4 and NKX2-5 interactome by BioID. Reporter gene assays were conducted to examine combinatorial effects of GATA-targeted compounds and bromodomain and extraterminal domain (BET) inhibition on chamber-specific gene expression.
resultsGATA4-targeted compounds 3i-1000 and 3i-1103 were identified as differential modulators of atrial and ventricular gene expression. More detailed structure-function analysis revealed a distinct subclass of GATA4/NKX2-5 inhibitory compounds with an acetyl lysine-like domain that contributed to ventricular cells (%Myl2-eGFP+). Additionally, BioID analysis indicated broad interaction between GATA4 and BET family of proteins, such as BRD4. This indicated the involvement of epigenetic modulators in the regulation of GATA-dependent transcription. In this line, reporter gene assays with combinatorial treatment of 3i-1000 and the BET bromodomain inhibitor (+)-JQ1 demonstrated the cooperative role of GATA4 and BRD4 in the modulation of chamber-specific cardiac gene expression.
conclusionsCollectively, these results indicate the potential for therapeutic alteration of cell fate decisions and pathological gene regulatory networks by GATA4-targeted compounds modulating chamber-specific transcriptional programs in multipotent cardiac progenitor cells and cardiomyocytes. The compound scaffolds described within this study could be used to develop regenerative strategies for myocardial regeneration.
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