bims-ecemfi Biomed News
on ECM and fibroblasts
Issue of 2025–08–24
eight papers selected by
Badri Narayanan Narasimhan, University of California, San Diego
  1. Substrate viscoelasticity regulates fibroblast adhesion and migration.
  2. Anisotropic liquid crystalline hydrogels direct 2D and 3D myoblast alignment.
  3. Cellular Responses to Nanoscale Topography Mediated Through the RhoA/ROCK Pathway.
  4. Agent-based modeling of macrophage-fibroblast interactions in the immune response to biomaterials.
  5. Measurement of tissue viscosity to relate force and motion in collective cell migration.
  6. 3D printing-biomimetic local stiff niche enhances glycolysis to boost PDAC cell stem-like phenotype via N6-methyladenosine-suppressed YAP1 mRNA decay.
  7. Form Follows Function: A New Paradigm of Pancreatic Cancer Progression.
  8. Functional Self-Immolative Hydrogels with Dendritic Cross-Linkers for Controlled Drug Delivery.
  1. Biointerphases. 2025 Jul 01. pii: 041010. [Epub ahead of print]20(4):
    Substrate viscoelasticity regulates fibroblast adhesion and migration.
    Neha Paddillaya, Akshar Rao, Anshul Shrivastava, Imnatoshi Jamir, Kundan Sengupta, Namrata Gundiah.
      Mechanical properties of the extracellular matrix (ECM) modulate cell-substrate interactions and influence cellular behaviors such as contractility, migration, and proliferation. Although the effects of substrate stiffness on mechanobiology have been well studied, the role of ECM viscoelasticity in fibrotic progression remains less understood. To examine how viscoelasticity affects the biophysical properties and regulates signaling of human mammary fibroblasts, we engineered elastic (E) and viscoelastic (VE) polyacrylamide hydrogels with comparable storage moduli (∼14.52 ± 1.03 kPa) but distinctly different loss moduli; mean loss moduli for VE gels was 36.9% higher at 0.05 Hz than E gels. Fibroblasts cultured on E hydrogels spread extensively (2428.93 ± 864.71 μm2), developed prominent stress fibers with higher zyxin intensity, and generated higher traction stresses (2931.57 ± 1732.61 Pa). In contrast, fibroblasts on VE substrates had 54.2% smaller focal adhesion areas, exhibited 51.8% lower critical adhesion strengths, and generated 21% lower traction stresses (p < 0.001). These substrates also promoted migration and showed enhanced proliferation with reduced Yes-associated protein (YAP) activity, suggesting a mechanotransduction shift that may involve alternative signaling pathways. In contrast, E substrates showed YAP nuclear translocation, consistent with greater cytoskeletal tension and contractility. These findings highlight the importance of energy dissipation mechanisms in regulating fibroblast function on substrates mimicking the fibrotic milieu. Our results demonstrate that tuning the ECM viscoelasticity is a useful strategy to regulate cell behaviors in tissue-engineered scaffolds and develop better disease modeling for regenerative medicine.
    DOI:  https://doi.org/10.1116/6.0004585
  2. Adv Funct Mater. 2025 Aug 07. pii: e18226. [Epub ahead of print]
    Anisotropic liquid crystalline hydrogels direct 2D and 3D myoblast alignment.
    Nathaniel P Skillin, Lorin Danielsen, Bruce E Kirkpatrick, Jonathan D Hoang, Lea Pearl Hibbard, Kristi S Anseth, Timothy J White.
      Tissue development and regeneration are governed by processes that span subcellular signaling, cell-cell interactions, and the integrated mechanical properties of cellular collectives with their extracellular matrix. Synthetic biomaterials that can emulate the hierarchical structure and supracellular mechanics of living systems are paramount to the realization of regenerative medicine. Recent reports detail directed cell alignment on mechanically anisotropic but stiff liquid crystalline polymer networks (LCNs). While compelling, the potential implementation of these materials as tissue engineering scaffolds may be hindered by the orders of magnitude larger stiffness than most soft tissue. Accordingly, this report prepares liquid crystalline hydrogels (LCHs) that synergize the anisotropic mechanical properties intrinsic to LCNs with the cytocompatibility and soft mechanics of PEG hydrogels. LCH are prepared via sequential oligomerization and photopolymerization reactions between liquid crystalline (LC) monomers and poly(ethylene glycol) (PEG)-dithiol. Despite their low liquid crystalline content, swollen LCH oligomers are amenable to rheological alignment via direct ink write 3D printing. Mechanically anisotropic LCHs support C2C12 myoblast culture on their surface and direct their alignment in the stiffest direction. Further, C2C12s can be encapsulated within LCH oligomers and 3D-printed, whereby mechanical anisotropy of the LCH directs myoblast polarization in 3D.
    Keywords:  3D bioprinting; anisotropic hydrogel; cellular alignment; liquid crystalline; tissue engineering
    DOI:  https://doi.org/10.1002/adfm.202518226
  3. Small. 2025 Aug 18. e05685
    Cellular Responses to Nanoscale Topography Mediated Through the RhoA/ROCK Pathway.
    Erik N Schaumann, Nam Heon Cho, Teri W Odom.
      Nanotopography exhibits strong effects on cellular properties such as cytoskeletal organization and endocytosis. Responses to topographical cues can propagate into cell-scale characteristics like cortical stiffness as well as systemic effects like inflammation and implant rejection; however, the biological pathways governing these effects remain comparatively unknown. Here we show how the RhoA/ROCK pathway can regulate responses to nanotopographical features vis-à-vis cellular tension. 2D arrays of hemispherical gold nanoparticles are combined with epithelial cells to determine how up- and down-regulating RhoA activity influences cellular responses. It is found that higher RhoA activity correlates with increased tension and decreased membrane conformality, actin reorganization, and endocytosis. Also, increased tension produces large focal adhesions in cells not typically observed from substrate patterns. Conversely, reducing tension by lowering RhoA activity results in increased membrane conformality around the nanoparticles as well as actin and endocytosis colocalization with nanoparticle sites. This study provides a critical connection between biomolecular regulators of cell mechanics, in particular RhoA, and cellular responses to nanoscale topographical features.
    Keywords:  RhoA; cytoskeleton; nanoparticles; nanoscale curvature; nanotopography
    DOI:  https://doi.org/10.1002/smll.202505685
  4. PLoS One. 2025 ;20(8): e0329186
    Agent-based modeling of macrophage-fibroblast interactions in the immune response to biomaterials.
    Jennifer Riccio, Luca Presotto, Shir Bahiri, Liad Doniza, Donato Inverso, Laura Sironi, Uri Nevo, Giuseppe Chirico.
      Foreign body reaction (FBR) denotes the reaction to the implantation of a biomaterial into the body. It triggers cascades of responses in the tissue and involves different cell types including, among others, macrophages, fibroblasts and endothelial cells. Macrophages regulate the inflammatory and healing processes. They exhibit a variety of functional phenotypes (or states) induced by the stimulus they receive and the microenvironment. This polarization process is governed by chemical mediators, known as cytokines, that are secreted by the macrophage itself and induce cellular activation and recruitment. Cytokines determine the macrophage phenotype within a heterogeneous range that spans between two extremes: pro-inflammatory or M1 and anti-inflammatory (or pro-healing) or M2. Fibroblasts are recruited in response to cytokine secretion and play a crucial role in tissue remodeling. These cells generate key components of the extracellular matrix (ECM), such as elastin, fibrin, and collagen, and have the ability to isolate the implanted biomaterial from surrounding tissue by encapsulating it within a fibrotic layer. The formation of this fibrotic capsule is a major factor contributing to the failure of many biomaterials. Macrophage and fibroblasts interact in tissues both in physiological and pathological conditions. One of the major signaling factor is the colony-stimulating factor 1 (CSF1) and its specific receptor (CSF1R). In the past, simulation works have focused only on the description of the phenotype transition from M1 to M2 for macrophages, possibly connected to physiological and pathological conditions (e.g. hypoxia), but neglecting the relevant macrophage/fibroblast interaction. Our long term aim is to exploit an agent-based (AB) modeling approach to develop a predictive digital twin for simulating the response over time of the cell populations involved in a FBR. Our first step in this direction is the explicit introduction of the interaction between macrophages and fibroblasts. To achieve this goal, we consider here at first the existing ordinary differential equation (ODE) and AB models, that simulate intra- and inter-cellular dynamics for macrophages, respectively. We validate them against in vitro data taken from experiments that recapitulate the reaction to a pathogen and in vivo data taken from the literature. This approach highlights a better agreement of the AB model over the ODE models taken into account in our study. Therefore, we propose a more advanced and comprehensive simulation platform based on AB modeling, which also includes fibroblasts and their mutual interaction with macrophages, as well as fibrosis resulting from the implantation of a biomaterial, allowing us to simulate in vivo scenarios. We validate this tool on experimental results from the literature finding a remarkable agreement. The application of this extended AB model allows us to replicate the kinetics of the cell populations involved, including, among others, the effect of different types of stimulus, chemotaxis, recruitment, and formation of the fibrotic capsule typical of the chronic FBR.
    DOI:  https://doi.org/10.1371/journal.pone.0329186
  5. ArXiv. 2025 Aug 15. pii: arXiv:2508.11518v1. [Epub ahead of print]
    Measurement of tissue viscosity to relate force and motion in collective cell migration.
    Molly McCord, Jacob Notbohm.
      In tissue development, wound healing, and cancer invasion, coordinated cell motion arises from active forces produced by the cells. The relationship between force and motion remains unclear, however, because the forces are a sum active and passive contributions. Here, we show that the active forces can be decoupled from the passive by careful investigation of the distribution of shear stress against strain rate. With this method, we show experimentally that the order of magnitude of passive tissue viscosity is 100 Pa-hr and that increasing (decreasing) the actomyosin cytoskeleton and cell-cell adhesions increase (decrease) the magnitude of tissue viscosity. These results establish tissue viscosity as a meaningful way to describe the mechanical behavior of epithelial tissues, and demonstrate a direct relationship between tissue microstructure and material properties. By providing the first experimental measurement of tissue viscosity, our study separates the active and passive components of stress, in turn clarifying the relationship between force and motion and providing a new means of identifying how active cell forces evolve in space and time.
  6. Mater Today Bio. 2025 Oct;34 102176
    3D printing-biomimetic local stiff niche enhances glycolysis to boost PDAC cell stem-like phenotype via N6-methyladenosine-suppressed YAP1 mRNA decay.
    Di Wu, Xiaoqi Guan, Tao Yang, Jiashuai Yan, Biwen Zhu, Junchao Zhou, Yibing Guo, Yuhua Lu.
      Cancer stem cells (CSCs), the primary source of therapy resistance in pancreatic ductal adenocarcinoma (PDAC), exist in a dynamic equilibrium through tumor microenvironment (TME)-driven plasticity. However, the stiffness heterogeneity of TME within PDAC functions on tumor cell stem-like phenotypes remains unclear. Bioinformatics, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, of CSCs identified from spatial transcriptomic and single-cell datasets of PDAC lesions exhibited activated mechanical and glycolytic pathways. Detected by the nano-indenter, PDAC tissue exhibited significant stiffness heterogeneity (200-6000 Pa). Further, biomimetic local stiffness niches were engineered using the digital light-processing (DLP) 3D-printing technology and the desmoplastic bioink (gelatin methacrylate & hyaluronic acid methacrylate, GelMA&HAMA) encapsulating PDAC cells, which permits modulation of mechanical properties without altering the biochemical ligand density. Stemness markers (NANOG, OCT4), glycolysis genes (HK2, LDHA), YAP1, and N6-methyladenosine (m6A) regulators (METTL14, IGF2BP3) were evaluated via qRT-PCR and immunofluorescence. Functional assays of glycolysis and stem-like phenotype were also conducted. Dot blot, RNA stability assay, western blot, and RIP assay were exploited to clarify the level and the function of m6A modification. The local stiff niche enhanced the stem-like phenotype of PDAC cells via YAP1-boosted glycolysis. Mechanistically, local stiff niche elevated the YAP1 level via m6A (METTL14/IGF2BP3)-stabilized YAP1 mRNA, linking mechanical inputs to glycolytic-stem-like phenotype adaptations. Collectively, the local stiff niches may drive the emergence of CSCs through epigenetic and metabolic reprogramming in PDAC mechanobiology. This provides new insights for developing more precise therapeutic strategies targeting PDAC mechanical heterogeneity.
    Keywords:  3D printing; Glycolysis; PDAC stiffness heterogeneity; Stem-like phenotype; YAP1; m6A
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102176
  7. bioRxiv. 2025 Aug 13. pii: 2025.08.12.667175. [Epub ahead of print]
    Form Follows Function: A New Paradigm of Pancreatic Cancer Progression.
    William Gasper, Giada Pontecorvi, Zhikai Chi, Sebastian Enrico, Lily Goodman, Haneen Amarneh, Evelyn Mazzarelli, Joshua Thomas, Lucia Zhang, Rachel Handloser, Seth LeCates, Ana Lucia Tomescu, Francesca Rossi, Myla Sykes, Anjali Bhatt, Nicholas Fazio, Alessandro Bifolco, Nafeesah Fatimah, Austin Seamann, Cheryl Lewis, Shelby Melton, Herbert J Zeh, Megan B Wachsmann, Dario Ghersi, Matteo Ligorio.
      Pancreatic ductal adenocarcinoma (PDAC) exhibits a distinctive propensity to invade nearby organs and infiltrate large blood vessels, even in the absence of distant metastasis. While the genetic and transcriptomic drivers of PDAC progression have been well studied, the mechanisms by which these molecular changes translate into functional, invasive behavior remain largely unknown. Here, we uncover a striking level of tissue organization, characterized by previously unrecognized spatial and geometric properties within and among tumor structures. Leveraging the first large-scale, AI-assisted, human-curated PDAC atlas from hematoxylin and eosin (H&E) images, we annotated, classified, and characterized 144,474 malignant and normal structures from treatment-naive (n=118) and neoadjuvant-treated PDAC patients (n=50). Additionally, we developed a new computational tool, SHAPE, to investigate PDAC aggressiveness through a comprehensive geometrization of cancer progression. Using traditional H&E-stained slides and three-dimensional (3D) tissue reconstruction experiments, we observed that invading tumor structures display an eccentric morphology with pronounced local angular coherence. These geometric and spatial properties revealed coherent architectural patterns, with invasive structures closely tracking vessels and nerves as they infiltrate surrounding tissue. Mechanistically, integration of morphological features from 39,045annotated tumor structures with whole-genome and RNA sequencing data revealed that PDACs with numerous eccentric structures exhibit increased copy number alterations (CNAs), loss of heterozygosity (LoH) on the p-arm of chromosome 17, and a quasi-mesenchymal/basal-like molecular subtype. Spatial transcriptomic analysis of 1,650 tumor structures from six additional PDAC patients further confirmed upregulation of invasive cellular programs within highly eccentric structures, such as epithelial-to-mesenchymal transition (EMT), angiogenesis, coagulation, and complement pathways, underscoring their infiltrative nature. Finally, cross-validation of our AI-based method enabled a fully automated, highly interpretable computational approach to assist pathologists and clinicians in evaluating neoadjuvant chemotherapy response, predicting patient survival, and guiding chemotherapy in adjuvant settings. Collectively, these findings deepen our understanding of PDAC progression, identify a new hallmark of tumor architecture, and pave the way for full integration of AI-driven morphology-based approaches into clinical workflows to improve the management of PDAC patients.
    DOI:  https://doi.org/10.1101/2025.08.12.667175
  8. Chem Mater. 2025 Aug 12. 37(15): 5814-5824
    Functional Self-Immolative Hydrogels with Dendritic Cross-Linkers for Controlled Drug Delivery.
    Silvia Muñoz-Sánchez, Jue Gong, Francisco Javier de la Mata, Elizabeth R Gillies, Sandra García-Gallego.
      In the biomedical field, the design of materials with controlled degradation is highly desired. Herein, we present a family of dendritic hydrogels accomplished through copper-assisted azide-alkyne cycloaddition click reaction between dendritic cross-linkers and complementary linear polymers. As cross-linkers, an innovative family of bifunctional carbosilane dendrimers was designed for this purpose, bearing multiple alkyne groups available for network formation as well as pendant hydroxyl groups for postfunctionalization. Additionally, different azide-pendant polymers were employed, including difunctional poly-(ethylene glycol) with cleavable and noncleavable nature, as well as poly-(ethyl glyoxylate) with and without self-immolative behavior. The rational design of the dendritic hydrogels, through the careful selection of these two components, enabled an accurate manipulation of properties like swelling and mechanical properties. The network degradation could be tuned from a few hours, for a traditional ester-cleavable dendritic hydrogel, to several days under pH-controlled conditions, for the self-immolative hydrogel (SIH). The impact of network degradation on the release of curcumin as a model drug was also confirmed. This work showcased the potential of dendritic SIHs for biomedical applications.
    DOI:  https://doi.org/10.1021/acs.chemmater.5c01006
This page is being maintained by Thomas Krichel. It was last updated on 2025‒09‒14 at 0:32.