ArticleProceedings of the National Academy of Sciences of the United States of America2013
Hydrogels preserve native phenotypes of valvular fibroblasts through an elasticity-regulated PI3K/AKT pathway.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 93 papers.
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Who cites it
93 citing papers in PubMed, 162 citations in OpenAlex.
- From biomechanical mechanisms to clinical reasoning: Deciphering mechanobiological drivers of aortic valve calcification for precision therapy.Mechanobiology in medicine · 2026Review
- Mechanical gating of tendon fibrogenic transcription in systemic sclerosis.Nature communications · 2026Article
- PTEN Regulates Myofibroblast Activation in Valvular Interstitial Cells Based on Subcellular Localization.Advanced biology · 2025Article
- Determining sex differences in aortic valve myofibroblast responses to drug combinations identified using a digital medicine platform.Science advances · 2025Article
- The mechanobiology of fibroblast activation in disease.APL bioengineering · 2025Review
- Kynurenine acts as a signaling molecule to attenuate pulmonary fibrosis by enhancing the AHR-PTEN axis.Journal of advanced research · 2025Article
- Thymosin Beta-4 Modulates Cardiac Remodeling by Regulating ROCK1 Expression in Adult Mammals.International journal of molecular sciences · 2025Article
- Automated prediction of fibroblast phenotypes using mathematical descriptors of cellular features.Nature communications · 2025Article
- Secreted Cytokines From Inflammatory Macrophages Modulate Sex Differences in Valvular Interstitial Cells on Hydrogel Biomaterials.Journal of biomedical materials research. Part A · 2025Article
- Photoresponsive Chemistries for User-Directed Hydrogel Network Modulation to Investigate Cell-Matrix Interactions.Accounts of chemical research · 2025Review
- Fibroblast PI3K/AKT signaling and extracellular matrix homeostasis: mechanisms, targets, and delivery challenges.Frontiers in cell and developmental biology · 2025Review
- A Biomimetic Leaflet Scaffold for Aortic Valve Remodeling.Advanced healthcare materials · 2024Article
- Dynamic reporters for probing real-time activation of human fibroblasts from single cells to populations.APL bioengineering · 2024Article
- Preservation of human heart valves for replacement in children with heart valve disease: past, present and future.Cell and tissue banking · 2024Review
- Implications of Cellular Mechanical Memory in Bioengineering.ACS biomaterials science & engineering · 2023Review
- Macrophages and fibroblasts in foreign body reactions: How mechanical cues drive cell functions?Materials today. Bio · 2023Review
- Effect of distinct ECM microenvironments on the genome-wide chromatin accessibility and gene expression responses of hepatic stellate cells.Acta biomaterialia · 2023Article
- A roadmap for developing and engineeringBiophysics reviews · 2023Review
- Ion Channels in the Development and Remodeling of the Aortic Valve.International journal of molecular sciences · 2023Review
- The Stiffness-Sensitive Transcriptome of Human Tendon Stromal Cells.Advanced healthcare materials · 2023Article
33 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 3 institutions in 3 countries.
Funding
Abstract
Matrix elasticity regulates proliferation, apoptosis, and differentiation of many cell types across various tissues. In particular, stiffened matrix in fibrotic lesions has been shown to promote pathogenic myofibroblast activation. To better understand the underlying pathways by which fibroblasts mechano-sense matrix elasticity, we cultured primary valvular interstitial cells (VICs) isolated from porcine aortic valves on poly(ethylene glycol)-based hydrogels with physiologically relevant and tunable elasticities. We show that soft hydrogels preserve the quiescent fibroblast phenotype of VICs much better than stiff plastic plates. We demonstrate that the PI3K/AKT pathway is significantly up-regulated when VICs are cultured on stiff gels or tissue culture polystyrene compared with freshly isolated VICs. In contrast, myofibroblasts de-activate and pAKT/AKT decreases as early as 2 h after reducing the substrate modulus. When PI3K or AKT is inhibited on stiff substrates, myofibroblast activation is blocked. When constitutively active PI3K is overexpressed, the myofibroblast phenotype is promoted even on soft substrates. These data suggest that valvular fibroblasts are sensing the changes in matrix elasticity through the PI3K/AKT pathway. This mechanism may be used by other mechano-sensitive cells in response to substrate modulus, and this pathway may be a worthwhile target for treating matrix stiffness-associated diseases. Furthermore, hydrogels can be designed to recapitulate important mechanical cues in native tissues to preserve aspects of the native phenotype of primary cells for understanding basic cellular responses to biophysical and biochemical signals, and for tissue-engineering applications.
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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.