ArticleAmerican journal of physiology. Heart and circulatory physiology2024
Substrate stiffness modulates cardiac fibroblast activation, senescence, and proinflammatory secretory phenotype.
Article in American journal of physiology. Heart and circulatory physiology, 2024. 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, 31 citations in OpenAlex.
- CAR T cell therapy beyond cancer: current status, challenges and future prospects.Signal transduction and targeted therapy · 2026Review
- Functional hydrogels in cardiovascular therapy: Design, applications and clinical challenges (Review).International journal of molecular medicine · 2026Review
- Establishing Primary Cultures of Adult Mouse Cardiac Fibroblasts: A Comparative Evaluation of Three Experimental Protocols.International journal of molecular sciences · 2026Article
- Substrate Stiffness and Viscoelasticity Influence Fibroblast Senescence.Journal of biomedical materials research. Part A · 2026Article
- Multicellular senescence programs in the aged heart.Journal of molecular and cellular cardiology plus · 2026Review
- Atorvastatin Attenuates Human Cardiac Fibroblast Activation, with Associated Changes in GATA4/MEF2C and Selected Fibrosis-Related microRNAs.International journal of molecular sciences · 2026Article
- Immunometabolism in Cardiac Remodeling: Mechanisms and Therapeutic Perspectives.International journal of molecular sciences · 2026Review
- Review
- Matrix viscoelasticity regulates dermal fibroblast activation in a three-dimensional fibrillar microenvironment.bioRxiv : the preprint server for biology · 2026Article
- Left ventricular hypertrophy and myocardial fibrosis in heart failure with preserved ejection fraction: mechanisms and treatment.European heart journal · 2026Review
- Developing a protocol to counteract spontaneous in vitro activation of intestinal fibroblasts using design of experiments.npj biomedical innovations · 2026Article
- The Heterogeneity and Function of Stromal Cells in the Tumor Microenvironment.Research (Washington, D.C.) · 2026Review
- Article
- Regulation of Tissue Regeneration by Immune Microenvironment-Fibroblast Interactions.International journal of molecular sciences · 2025Review
- Substrate stiffness-dependent metabolic reprogramming of iPSC-derived cardiomyocytes on physiological PDMS polymers.Metabolic engineering communications · 2025Article
- The controversial role of senescence-associated secretory phenotype (SASP) in cancer therapy.Molecular cancer · 2025Review
- Substrate Stiffness Modulates Fibroblast Extracellular Vesicle Secretion Via Mechanotransduction Pathways.Small (Weinheim an der Bergstrasse, Germany) · 2025Article
- Identification of prognostic genes associated with sphingosine-1-phosphate in gastric cancer to construct a risk mode.Translational cancer research · 2025Article
- RNA 5-Methylcytosine Modification in Myocardial Fibrosis.Reviews in cardiovascular medicine · 2025Review
- The states of senescent cells.Biochemical Society transactions · 2025Review
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
In vitro cultures of primary cardiac fibroblasts (CFs), the major extracellular matrix (ECM)-producing cells of the heart, are used to determine molecular mechanisms of cardiac fibrosis. However, the supraphysiologic stiffness of tissue culture polystyrene (TCPS) triggers the conversion of CFs into an activated myofibroblast-like state, and serial passage of the cells results in the induction of replicative senescence. These phenotypic switches confound the interpretation of experimental data obtained with cultured CFs. In an attempt to circumvent TCPS-induced activation and senescence of CFs, we used poly(ethylene glycol) (PEG) hydrogels as cell culture platforms with low and high stiffness formulations to mimic healthy and fibrotic hearts, respectively. Low hydrogel stiffness converted activated CFs into a quiescent state with a reduced abundance of α-smooth muscle actin (α-SMA)-containing stress fibers. Unexpectedly, lower substrate stiffness concomitantly augmented CF senescence, marked by elevated senescence-associated β-galactosidase (SA-β-Gal) activity and increased expression of p16 and p21, which are antiproliferative markers of senescence. Using dynamically stiffening hydrogels with phototunable cross-linking capabilities, we demonstrate that premature, substrate-induced CF senescence is partially reversible. RNA-sequencing analysis revealed widespread transcriptional reprogramming of CFs cultured on low-stiffness hydrogels, with a reduction in the expression of profibrotic genes encoding ECM proteins, and an attendant increase in expression of NF-κB-responsive inflammatory genes that typify the senescence-associated secretory phenotype (SASP). Our findings demonstrate that alterations in matrix stiffness profoundly impact CF cell state transitions, and suggest mechanisms by which CFs change phenotype in vivo depending on the stiffness of the myocardial microenvironment in which they reside.
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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.