ArticleBioengineering & translational medicine2022
Extracellular matrix stiffness controls cardiac valve myofibroblast activation through epigenetic remodeling.
Article in Bioengineering & translational medicine, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 39 citations in OpenAlex.
- Nuclear mechanotransduction: tools for mechanical perturbation and chromatin characterization.Nucleus (Austin, Tex.) · 2026Review
- From biomechanical mechanisms to clinical reasoning: Deciphering mechanobiological drivers of aortic valve calcification for precision therapy.Mechanobiology in medicine · 2026Review
- Cardiac microphysiological systems in cardiovascular research: Construction paradigms, maturation trajectories, and translational frontiers.Bioengineering & translational medicine · 2026Review
- A Circuit of Mechanically Regulated Transcription Factors Balances Regenerative and Fibrotic Memory of Mesenchymal Stromal Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- ECM-Stiffness Mediated Persistent Fibroblast Activation Requires Integrin and Formin Dependent Chromatin Remodeling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Review
- Mechanical forces orchestrate the epigenetic landscape of oral mesenchymal stem/progenitor cell fate in dental and periodontal tissues.Frontiers in cell and developmental biology · 2026Review
- EP300/CREBBP induces osteogenic differentiation of valve interstitial cells by promoting the SPP1 expression in calcific aortic valve disease.Cytotechnology · 2025Article
- PTEN Regulates Myofibroblast Activation in Valvular Interstitial Cells Based on Subcellular Localization.Advanced biology · 2025Article
- Increased matrix stiffness promotes fibrogenesis of hepatic stellate cells through AP-1-induced chromatin priming.Communications biology · 2025Article
- Interplay between extracellular matrix mechanics and cell function in mechanobiology.Current opinion in biomedical engineering · 2025Article
- Renal tubular epithelial cell-derived Exosomal miR-330-3p plays a key role in fibroblast activation and renal fibrosis by regulating CREBBP.Stem cell research & therapy · 2025Article
- Advances in Pathophysiological Mechanisms of Degenerative Aortic Valve Disease.Cardiology research · 2025Review
- Automated prediction of fibroblast phenotypes using mathematical descriptors of cellular features.Nature communications · 2025Article
- Y chromosome-linked UTY modulates sex differences in valvular fibroblast methylation in response to nanoscale extracellular matrix cues.Science advances · 2025Article
- Secreted Cytokines From Inflammatory Macrophages Modulate Sex Differences in Valvular Interstitial Cells on Hydrogel Biomaterials.Journal of biomedical materials research. Part A · 2025Article
- Fatty Acid Oxidation-Glycolysis Metabolic Transition Affects ECM Homeostasis in Silica-Induced Pulmonary Fibrosis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The role of YAP/TAZ mechanosignaling in trabecular meshwork and Schlemm's canal cell dysfunction.Vision research · 2024Review
- Postprandial cardiac hypertrophy is sustained by mechanics, epigenetic, and metabolic reprogramming in pythons.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- The Myofibroblast Fate of Therapeutic Mesenchymal Stromal Cells: Regeneration, Repair, or Despair?International journal of molecular sciences · 2024Review
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 1 country.
Funding
Abstract
Aortic valve stenosis (AVS) is a progressive fibrotic disease that is caused by thickening and stiffening of valve leaflets. At the cellular level, quiescent valve interstitial cells (qVICs) activate to myofibroblasts (aVICs) that persist within the valve tissue. Given the persistence of myofibroblasts in AVS, epigenetic mechanisms have been implicated. Here, we studied changes that occur in VICs during myofibroblast activation by using a hydrogel matrix to recapitulate different stiffnesses in the valve leaflet during fibrosis. We first compared the chromatin landscape of qVICs cultured on soft hydrogels and aVICs cultured on stiff hydrogels, representing the native and diseased phenotypes respectively. Using assay for transposase-accessible chromatin sequencing (ATAC-Seq), we found that open chromatin regions in aVICs were enriched for transcription factor binding motifs associated with mechanosensing pathways compared to qVICs. Next, we used RNA-Seq to show that the open chromatin regions in aVICs correlated with pro-fibrotic gene expression, as aVICs expressed higher levels of contractile fiber genes, including myofibroblast markers such as alpha smooth muscle actin (αSMA), compared to qVICs. In contrast, chromatin remodeling genes were downregulated in aVICs compared to qVICs, indicating qVICs may be protected from myofibroblast activation through epigenetic mechanisms. Small molecule inhibition of one of these remodelers, CREB Binding Protein (CREBBP), prevented qVICs from activating to aVICs. Notably, CREBBP is more abundant in valves from healthy patients compared to fibrotic valves. Our findings reveal the role of mechanical regulation in chromatin remodeling during VIC activation and quiescence and highlight one potential therapeutic target for treating AVS.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.