bims-ecemfi Biomed News
on ECM and fibroblasts
Issue of 2025–03–30
seven papers selected by
Badri Narayanan Narasimhan, University of California, San Diego
  1. Matrix degradation enhances stress relaxation, regulating cell adhesion and spreading.
  2. Breast cancer extracellular matrix invasion depends on local mechanical loading of the collagen network.
  3. Tension anisotropy drives fibroblast phenotypic transition by self-reinforcing cell-extracellular matrix mechanical feedback.
  4. Rheological transition driven by matrix makes cancer spheroids resilient under confinement.
  5. Dynamic hydrogels for biofabrication: A review.
  6. Cell compression - relevance, mechanotransduction mechanisms and tools.
  7. Confinement by Liquid-Liquid Interface Replicates In Vivo Neutrophil Deformations and Elicits Bleb-Based Migration.
  1. Proc Natl Acad Sci U S A. 2025 Apr;122(13): e2416771122
    Matrix degradation enhances stress relaxation, regulating cell adhesion and spreading.
    Badri Narayanan Narasimhan, Stephanie I Fraley.
      In native extracellular matrices (ECM), cells utilize matrix metalloproteinases (MMPs) to degrade and remodel their microenvironment. Accordingly, synthetic matrices have been engineered to permit MMP-mediated cleavage, facilitating cell spreading, migration, and interactions. However, the interplay between matrix degradability and mechanical properties remains underexplored. We hypothesized that MMP activity induces immediate mechanical alterations in the ECM, which are subsequently detected by cells. We observed that both fibrillar collagen and synthetic degradable matrices exhibit enhanced stress relaxation following MMP exposure. Cells responded to these variations in relaxation by modulating their spreading and focal adhesions. Furthermore, we demonstrated that stress relaxation and cell spreading can be precisely controlled through the rational design of matrix degradability. These findings establish a fundamental link between matrix degradability and stress relaxation, with potential implications for a broad spectrum of biological applications.
    Keywords:  collagen; degradability; extracellular matrix; matrix metalloproteinase; stress relaxation
    DOI:  https://doi.org/10.1073/pnas.2416771122
  2. J Mater Chem B. 2025 Mar 26.
    Breast cancer extracellular matrix invasion depends on local mechanical loading of the collagen network.
    Hanadi M Alqosiri, Hadeel M Alqasiri, Sara E Alqasire, Victor E Nava, Bidhan C Bandyopadhyay, Christopher B Raub.
      Active mechanical stresses in and around tumors affect cancer cell behavior and independently regulate cancer progression. To investigate the role of mechanical stress in breast cancer cell invasion, magnetic alginate beads loaded with iron oxide nanoparticles were coated with MDA-MB-231 breast cancer cells and embedded in a three-dimensional extracellular matrix (ECM) model subjected to an external magnetic field during culture. Bead displacement, cell shape and patterns of invasion of the collagen gel, and cell proliferation were assessed over 7 days of culture. The alginate beads swelled over the first 24 h in culture, creating circumferential stress akin to that created by tumor growth, while bead magnetic properties enabled local mechanical loading (compression, tension, and relaxation) and motion within the in vitro tissue constructs upon exposure to an external magnetic field. Beads displaced 0.2-1.6 mm through the collagen gels, depending on magnet size and distance, compressing the collagen network microstructure without gel mechanical failure. Invading cells formed a spatulate pattern as they moved into the compressed ECM region, with individual cells aligned parallel to the bead surface. During the first 24 hours of compressive magnetic force loading, invading cancer cells became round, losing elongation and ability to invade out from the bead surface, while still actively dividing. In contrast, cell invasion in unloaded constructs and in loaded constructs away from the compression region invaded as single cells, transversely outward from the bead surface. Finally, cell proliferation was 1.3× higher only after external magnet removal, which caused relaxation of mechanical stress in the collagen network. These findings indicate effects on breast cancer invasion of mechanical loading of ECM, both from compressive loading and from load relaxation. Findings point to the influence of mechanical stress on cancer cell behavior and suggest that relaxing mechanical stress in and around a tumor may promote cancer progression through higher proliferation and invasion.
    DOI:  https://doi.org/10.1039/d4tb01474j
  3. Nat Mater. 2025 Mar 24.
    Tension anisotropy drives fibroblast phenotypic transition by self-reinforcing cell-extracellular matrix mechanical feedback.
    Farid Alisafaei, Delaram Shakiba, Yuan Hong, Ghiska Ramahdita, Yuxuan Huang, Leanne E Iannucci, Matthew D Davidson, Mohammad Jafari, Jin Qian, Chengqing Qu, David Ju, Dashiell R Flory, Yin-Yuan Huang, Prashant Gupta, Shumeng Jiang, Aliza Mujahid, Srikanth Singamaneni, Kenneth M Pryse, Pen-Hsiu Grace Chao, Jason A Burdick, Spencer P Lake, Elliot L Elson, Nathaniel Huebsch, Vivek B Shenoy, Guy M Genin.
      Mechanical factors such as stress in the extracellular environment affect the phenotypic commitment of cells. Stress fields experienced by cells in tissues are multiaxial, but how cells integrate such information is largely unknown. Here we report that the anisotropy of stress fields is a critical factor triggering a phenotypic transition in fibroblast cells, outweighing the role of stress amplitude, a factor previously described to modulate such a transition. Combining experimental and computational approaches, we identified a self-reinforcing mechanism in which cellular protrusions interact with collagen fibres to establish tension anisotropy. This anisotropy, in turn, stabilizes the protrusions and enhances their contractile forces. Disruption of this self-reinforcing process, either by reducing tension anisotropy or by inhibiting contractile protrusions, prevents the phenotypic conversion of fibroblasts to contractile myofibroblasts. Overall, our findings support stress anisotropy as a factor modulating cellular responses, expanding our understanding of the role of mechanical forces in biological processes.
    DOI:  https://doi.org/10.1038/s41563-025-02162-5
  4. Life Sci Alliance. 2025 Jun;pii: e202402601. [Epub ahead of print]8(6):
    Rheological transition driven by matrix makes cancer spheroids resilient under confinement.
    Tavishi Dutt, Jimpi Langthasa, Monica Umesh, Satyarthi Mishra, Siddharth Bothra, Kottpalli Vidhipriya, Annapurna Vadaparty, Prosenjit Sen, Ramray Bhat.
      Cancer metastasis through confining peritoneal microenvironments is mediated by spheroids: clusters of disseminated cells. Ovarian cancer spheroids are frequently cavitated; such blastuloid morphologies possess an outer ECM coat. We investigated the effects of these spheroidal morphological traits on their mechanical integrity. Atomic force microscopy showed blastuloids were elastic compared with their prefiguring lumenless moruloid counterparts. Moruloids flowed through microfluidic setups mimicking peritoneal confinement, exhibited asymmetric cell flows during entry, were frequently disintegrated, and showed an incomplete and slow shape recovery upon exit. In contrast, blastuloids exhibited size-uncorrelated transit kinetics, rapid and efficient shape recovery upon exit, symmetric cell flows, and lesser disintegration. Blastuloid ECM debridement phenocopied moruloid traits including lumen loss and greater disintegration. Multiscale computer simulations predicted that higher intercellular adhesion and dynamical lumen make blastuloids resilient. Blastuloids showed higher E-cadherin expression, and their ECM removal decreased membrane E-cadherin localization. E-cadherin knockdown also decreased lumen formation and increased spheroid disintegration. Thus, the spheroidal ECM drives its transition from a labile viscoplastic to a resilient elastic phenotype, facilitating their survival within spatially constrained peritoneal flows.
    DOI:  https://doi.org/10.26508/lsa.202402601
  5. Biomaterials. 2025 Mar 18. pii: S0142-9612(25)00185-1. [Epub ahead of print]320 123266
    Dynamic hydrogels for biofabrication: A review.
    Runze Xu, Hon Son Ooi, Liming Bian, Liliang Ouyang, Wei Sun.
      Reversibly crosslinked dynamic hydrogels have emerged as a significant material platform for biomedical applications owing to their distinctive time-dependent characteristics, including shear-thinning, self-healing, stress relaxation, and creep. These physical properties permit the use of dynamic hydrogels as injectable carriers or three-dimensional printable bioinks. It is noteworthy that matrix dynamics can serve as physical cues that stimulate cellular processes. Therefore, dynamic hydrogels are preferred for tissue engineering and biofabrication, which seek to create functional tissue constructs that require regulation of cellular processes. This review summarizes the critical biophysical properties of dynamic hydrogels, various cellular processes and related mechanisms triggered by hydrogel dynamics, particularly in three-dimensional culture scenarios. Subsequently, we present an overview of advanced biofabrication techniques, particularly 3D bioprinting, of dynamic hydrogels for the large-scale production of tissue and organ engineering models. This review presents an overview of the strategies that can be used to expand the range of applications of dynamic hydrogels in biofabrication, while also addressing the challenges and opportunities that arise in the field. This review highlights the importance of matrix dynamics in regulating cellular processes and elucidates strategies for leveraging them in the context of biofabrication.
    Keywords:  3D bioprinting; Biofabrication; Bioink; Dynamic hydrogel; Tissue engineering
    DOI:  https://doi.org/10.1016/j.biomaterials.2025.123266
  6. J Cell Sci. 2025 Mar 15. pii: jcs263704. [Epub ahead of print]138(6):
    Cell compression - relevance, mechanotransduction mechanisms and tools.
    Laura M Faure, Valeria Venturini, Pere Roca-Cusachs.
      From border cell migration during Drosophila embryogenesis to solid stresses inside tumors, cells are often compressed during physiological and pathological processes, triggering major cell responses. Cell compression can be observed in vivo but also controlled in vitro through tools such as micro-channels or planar confinement assays. Such tools have recently become commercially available, allowing a broad research community to tackle the role of cell compression in a variety of contexts. This has led to the discovery of conserved compression-triggered migration modes, cell fate determinants and mechanosensitive pathways, among others. In this Review, we will first address the different ways in which cells can be compressed and their biological contexts. Then, we will discuss the distinct mechanosensing and mechanotransducing pathways that cells activate in response to compression. Finally, we will describe the different in vitro systems that have been engineered to compress cells.
    Keywords:   In vitro systems; Cytoskeleton; Mechanobiology; Mechanosensation; Mechanotransduction; Membrane
    DOI:  https://doi.org/10.1242/jcs.263704
  7. Adv Sci (Weinh). 2025 Mar 28. e2414024
    Confinement by Liquid-Liquid Interface Replicates In Vivo Neutrophil Deformations and Elicits Bleb-Based Migration.
    Jonathan H Schrope, Adam Horn, Kaitlyn Lazorchak, Clyde W Tinnen, Jack J Stevens, Mehtab Farooqui, Tanner Robertson, Jiayi Li, David Bennin, Terry Juang, Adeel Ahmed, Chao Li, Anna Huttenlocher, David J Beebe.
      Leukocytes forge paths through interstitial spaces by exerting forces to overcome confining mechanical pressures provided by surrounding cells. While such mechanical cues regulate leukocyte motility, engineering an in vitro system that models the deformable cellular environment encountered in vivo has been challenging. Here, microchannels are constructed with a liquid-liquid interface that exerts confining pressures similar to cells in tissues, and thus, is deformable by cell-generated forces. Consequently, the balance between migratory cell-generated and interfacial pressures determines the degree of confinement. Pioneer cells that first contact the interfacial barrier require greater deformation forces to forge a path for migration, and as a result migrate slower than trailing cells. Critically, resistive pressures are tunable by controlling the curvature of the liquid interface, which regulates motility. By granting cells autonomy in determining their confinement, and tuning environmental resistance, interfacial deformations match those of surrounding cells in vivo during interstitial neutrophil migration in a larval zebrafish model. It is discovered that neutrophils employ a bleb-based mechanism of force generation to deform a soft barrier exerting cell-scale confining pressures. In all, this work introduces a tunable in vitro material interface that replicates confining pressures applied by soft tissue environments.
    Keywords:  cell confinement; cell migration; immunology; mechanobiology; microfluidics; neutrophils; soft materials
    DOI:  https://doi.org/10.1002/advs.202414024
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