bims-ecemfi 2025-09-21 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2025–09–21
nine papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Actin Branching Regulates Cell Spreading and Force on Talin, but not Activation of YAP.
Extracellular Matrix Stiffness Conditions Glioblastoma Cells for Long-term Migration: Mechanical Memory as a Driver of Invasion and Recurrence in Glioblastoma.
Lung tissue viscoelasticity is preserved with bleomycin-induced fibrosis in mice.
Matrix and cytoskeletal tension gate stretch-induced calcium signaling.
Distinct Chemical Cues Reprogram Cellular and Multicellular Phenotypes in Ovarian Cancer Spheroids.
Collagen-Fibronectin Crosstalk in Engineered Matrices: Synergistic Assembly Orchestrates Fibrillar Morphogenesis and Cell Adhesion-Migration Dynamics.
Electrical stimulation directs formation of perfused vasculature in engineered tissues.
Incorporation of Visible Light-Responsive Push-Pull Azobenzene into Polymer Networks toward the Construction of Photodynamic Hydrogel Scaffolds.
Real-Time Monitoring of the Formation and Culture of Hybrid Cell-Microbiomaterial Spheroids Using Non-Faradaic Electrical Impedance Spectroscopy.

Cell Mol Bioeng. 2025 Aug;18(3-4): 271-282

Actin Branching Regulates Cell Spreading and Force on Talin, but not Activation of YAP.

Claudia Villalobos, Amir Sadeghifar, Jose Maggiorani, Juliet Delapena, Garrett McDaniel, Tristan P Driscoll.

   Purpose: Cells sense the mechanical properties of their environment through physical engagement and spreading, with high stiffness driving nuclear translocation of the mechanosensitive transcription factor YAP. Restriction of cell spread area or environmental stiffness both inhibit YAP activation and nuclear translocation. The Arp2/3 complex plays a critical role in polymerization of branched actin networks that drive cell spreading, protrusion, and migration. While YAP activation has been closely linked to cellular spreading, the specific role of actin branching in force buildup and YAP activation is unclear.
Methods: To assess the role of actin branching in this process, we measured cell spreading, YAP nuclear translocation, force on the adhesion adaptor protein Talin (FRET tension sensor), and extracellular forces (traction force microscopy, TFM) in 3T3 cells with and without inhibition of actin branching.
Results: The results indicate that YAP activation still occurs when actin branching and cell spreading is reduced. Interestingly, while actin de-branching resulted in decreased force on talin, relatively little change in average traction stress was observed, highlighting the distinct difference between molecular level and cellular level force regulation of YAP.
Conclusions: While cell spreading is a driver of YAP nuclear translocation, this is likely through indirect effects. Changes in cell spreading induced by actin branching inhibition do not significantly perturb YAP activation. Additionally, this work provides evidence that focal adhesion molecular forces are not a direct regulator of YAP activation.
Supplementary Information: The online version contains supplementary material available at 10.1007/s12195-025-00852-3.

Keywords:  Arp2/3; Contractility; Focal adhesion; YAP

DOI:  https://doi.org/10.1007/s12195-025-00852-3
Neuro Oncol. 2025 Sep 17. pii: noaf205. [Epub ahead of print]

Extracellular Matrix Stiffness Conditions Glioblastoma Cells for Long-term Migration: Mechanical Memory as a Driver of Invasion and Recurrence in Glioblastoma.

Paola Suarez-Meade, Rachel Whitehead, Steve Rosenfeld, Paula Schiapparelli, Konstantinos Konstantopoulos, Alfredo Quinones-Hinojosa.

  Extracellular matrix (ECM) stiffening correlates with tumor invasion in various cancer types, including glioblastoma (GBM). Increased matrix stiffness promotes a migratory phenotype through dysregulation of cell-ECM bidirectional communication. Exposure to stiffer environments is sensed by cells, which then adapt in ways that promote invasive behavior. These adaptive changes are imprinted onto the cells and persist even after they are placed in new, softer microenvironments via a process known as "mechanical memory". Mechanical memory is believed to be driven by mechanosensitive transcription factor activity and epigenetic remodeling. Glioblastoma (GBM) recurrence is linked to the ability of cells to disperse and infiltrate the surrounding healthy tissue. ECM stiffness in GBM is heterogeneous; it starts with a softer tumor core and becomes progressively stiffer towards the tumor's edges, potentially promoting sustained tumor invasion through mechanical memory. This review discusses the role of ECM stiffness in cancer cell behavior and the implications of ECM stiffening in GBM. We then describe the findings associated with mechanical memory and relay underlying mechanisms currently understood to drive the preservation of mechanically primed phenotypes. Lastly, we discuss how matrix stiffness can drive migratory phenotypes in GBM cells and the potential role that progressive ECM dysregulation at the tumor periphery can link the formation of invasive tumor niches to the aggressive, resistant, and mesenchymal-like phenotypes present in GBM recurrent tumors.

Keywords:  Brain Tumor; Epigenetics; Extracellular Matrix; Glioblastoma; Mechanical Memory; Stiffness

DOI:  https://doi.org/10.1093/neuonc/noaf205
bioRxiv. 2025 Sep 11. pii: 2025.09.06.674583. [Epub ahead of print]

Lung tissue viscoelasticity is preserved with bleomycin-induced fibrosis in mice.

Leilani R Astrab, Riley T Hannan, Mackenzie L Skelton, Jeffrey M Sturek, Steven R Caliari.

In pulmonary fibrosis, excessive scar tissue accumulates in the alveolar interstitial space, impairing gas exchange and compromising lung function. This fibrotic remodeling results in tissue stiffening, but more complex lung mechanical properties critical to tissue function, such as viscoelasticity and stress relaxation, remain poorly defined. To address this gap, we use the bleomycin aged mouse model to characterize both bulk and spatially-resolved viscoelastic mechanical properties of normal and fibrotic lungs. Our analysis reveals that while bleomycin-induced fibrosis leads to heterogeneously increased lung stiffness, viscoelasticity as measured by tan delta (ratio of loss to storage modulus) and stress relaxation timescales remains remarkably consistent as a function of both age and bleomycin treatment. This unexpected preservation of viscoelasticity despite fibrotic stiffening highlights a previously underappreciated mechanical phenotype of fibrotic lungs. To model these distinct mechanical features in vitro , we utilize a hyaluronic acid-based hydrogel system that largely recapitulates the viscoelastic mechanical properties observed in both normal and fibrotic lungs. These findings provide new insight into the mechanical consequences of fibrosis and establish a tunable in vitro hydrogel platform mimicking key tissue viscoelastic properties.

DOI: https://doi.org/10.1101/2025.09.06.674583
Acta Biomater. 2025 Sep 11. pii: S1742-7061(25)00680-4. [Epub ahead of print]

Matrix and cytoskeletal tension gate stretch-induced calcium signaling.

Patrick K Jaeger, Fabian S Passini, Barbara Niederoest, Maja Bollhalder, Sandro Fucentese, Jess G Snedeker.

  The extracellular matrix (ECM) and mechanical loading shape cellular behavior, yet their interaction remains obscure. We developed a dynamic proto-tissue model using human tendon cells and live-cell calcium imaging to study how ECM and cell mechanics regulate mechanotransduction. Stretch-induced calcium signaling served as a functional readout. We discovered that ascorbic acid-dependent ECM deposition is essential for proto-tissue maturation and the recovery of stretch-induced calcium signaling at physiological strains. ECM synthesis and mechanical integration enhanced stretch sensitivity, reducing the strain needed to trigger a calcium response from ∼40% in isolated cells to ∼5% in matured proto-tissues. A strong correlation between tissue rupture and onset calcium signaling indicates a mechanistic link to ECM damage. Disrupting ECM integrity, cell alignment, or cytoskeletal tension reduced mechanosensitivity, demonstrating the influence of ECM and cytoskeletal integration and mechanics on stretch-induced calcium signaling. Fundamentally, our work replicates calcium signaling observed in rodent tendon explants in vitro and bridges the gap between cell-scale and tissue-scale mechanotransduction. STATEMENT OF SIGNIFICANCE: The dysregulation of the tendon extracellular matrix is central to tendon disease, with controlled mechanical loading via physical therapy as the only established treatment. Tendon cells repair and maintain the matrix based on mechanical demands, yet how they sense loading-and how matrix or cytoskeleton mechanics influence this-remains unclear. Animal models are often impractical, and existing in vitro models lack physiological relevance. We developed a dynamic in vitro model that replicates load-induced calcium signaling, a physiological tendon cell response seen in rodent tendons, and show that matrix and cytoskeleton mechanics are key to load sensation. Anchored to a validated sensory response, our model enhances physiological relevance and offers a platform to study tendon degeneration and recovery mechanisms.

Keywords:  ECM–cell mechanical coupling; calcium signaling; cell mechanics; cytoskeletal tension; extracellular matrix; in vitro proto-tissue model; mechanotransduction; tendon

DOI:  https://doi.org/10.1016/j.actbio.2025.09.014
Small. 2025 Sep 16. e06120

Distinct Chemical Cues Reprogram Cellular and Multicellular Phenotypes in Ovarian Cancer Spheroids.

M Sreepadmanabh, Meenakshi Ganesh, Jimpi Langthasa, Ramray Bhat, Tapomoy Bhattacharjee.

  The self-organization of cellular collectives is crucial in development and cancer. Multicellular aggregation in cancer is associated with a higher efficiency of metastasis. However, it is not fully understood how mechanochemical microenvironmental cues affect the organization and stability of such ensembles. Here, using a model system of ovarian cancer spheroids, which temporally transit from solid, dysmorphic moruloids to structurally plastic, lumen-containing blastuloids, it is shown that the periodic volume fluctuations observed in blastuloids are driven by lumenal fluid influx and cell-cell junctional states. Furthermore, blastuloid cell states are reprogrammed, which enables them to rapidly recover from even complete structural disintegration and self-organize into fully lumenized ensembles. Using targeted chemical perturbations, two distinct cues are identified that regulate separate transition traits: calcium levels establish cell states cognate to, and pH regulates the fluctuation dynamics of blastuloid phenotypes. The work holds significant implications toward understanding mechanisms governing structural resilience and plasticity in complex cellular assemblies.

Keywords:  biochemical regulation; cancer spheroids; chemical reprogramming; multicellular collectives; ovarian cancer

DOI:  https://doi.org/10.1002/smll.202506120
Biomacromolecules. 2025 Sep 15.

Collagen-Fibronectin Crosstalk in Engineered Matrices: Synergistic Assembly Orchestrates Fibrillar Morphogenesis and Cell Adhesion-Migration Dynamics.

Yuan J Hou, Rui M Guo, Fang Li, De S Fan, Cheng Z Xu, Lian Zhu, Jun T Zhang, Ben M Wei, Hai B Wang.

The cooperative interplay between type I collagen (COL) and fibronectin (FN) in the extracellular matrix (ECM) guides both matrix organization and cell behavior. While COL-based materials are widely used, their limited capacity to integrate FN-mediated regulatory cues restricts functional biomimicry. Here, we investigate how COL/FN composites in distinct assembly states (monomeric vs fibrillar) differentially regulate cellular responses. Biophysical characterization confirmed FN binding to COL α chains promotes coassembly into hybrid fibrils with accelerated kinetics and enhanced mechanical rigidity. Strikingly, HT1080 cells exhibited opposing adhesion behaviors on monomeric versus fibrillar COL/FN matrices. In monomeric matrices, escalating FN ratios progressively reduced adhesion, while in fibrillar matrices, low-FN ratios enhanced adhesion synergistically. Cell migration followed an inverse pattern, with monomeric hybrids promoting motility and fibrillar matrices suppressing it. Our findings highlight that COL/FN assembly states, independent of compositional changes, dictate cell-matrix reciprocity through structural reconfiguration. This work establishes a paradigm for engineering ECM-inspired materials with phase-specific topographies to guide cellular decision-making, advancing applications in tissue regeneration and mechanobiology studies.

DOI: https://doi.org/10.1021/acs.biomac.5c01404
bioRxiv. 2025 Sep 03. pii: 2025.08.28.672965. [Epub ahead of print]

Electrical stimulation directs formation of perfused vasculature in engineered tissues.

Katarzyna A Grzelak, Ashley D Westerfield, Vardhman Kumar, Kasturi Chakraborty, Navaneeth Krishna Rajeeva Pandian, Christopher S Chen, Sangeeta N Bhatia.

Effective, rapid and functionally perfusable vascularization remains a major challenge in tissue engineering. Current approaches to generate vasculature in vitro require multipart fabrication methods or complex and costly media supplements, limiting their scalability. Here, we demonstrate that exogenous electrical stimulation (estim) offers a promising alternative by enhancing 3D vasculogenesis in engineered human tissues. Exposing 3D endothelial-fibroblast cocultures to pulsed estim promoted the formation of dense and branched vascular networks. In a microfluidic device model, we show that estim induces the formation of an interconnected vascular network that can be perfused, whereas unstimulated control networks remained less mature. Importantly, we demonstrate that upon implantation, estim-pretreated vascular grafts exhibit elevated anastomosis with host and perfusion with blood relative to the untreated grafts. In addition, we use estim to promote engraftment of a vascularized 3D liver construct. Mechanistically, we find that estim induces membrane hyperpolarization in endothelial cells via voltage-gated potassium (K V ) channels. Inhibiting K V channels abrogated estim's pro-vasculogenic effects in endothelial cells. Conversely, pharmacologically activating hyperpolarization induced endothelial responses even without estim, directly linking K V channel-mediated hyperpolarization as a key mechanism by which estim drives vascular assembly and function. Ultimately, our work establishes estim as a new orthogonal approach to promote formation of perfusable vasculature in engineered tissues.

DOI: https://doi.org/10.1101/2025.08.28.672965
ACS Macro Lett. 2025 Sep 19. 1418-1424

Incorporation of Visible Light-Responsive Push-Pull Azobenzene into Polymer Networks toward the Construction of Photodynamic Hydrogel Scaffolds.

Itsuki Miyaguni, Kenta Homma, Michiya Matsusaki.

Forces play vital roles in regulating cellular behavior, and integrins are prime examples that cells use to sense forces. Designer scaffolds have been developed to trigger integrin-mediated mechanotransduction to control cellular functions. However, current scaffolds lack spatiotemporal control of integrin mechanostimulation in a three-dimensional matrix. In this study, a photoresponsive hydrogel scaffold in which a cell-adhesive push-pull azobenzene was covalently loaded onto the hydrogel was synthesized. The cis-trans photoisomerization of azobenzene is expected to mechanostimulate the interaction of integrins with the cell-adhesive peptides (RGD peptide; arginine-glycine-aspartic acid) bound to azobenzene. The photoresponsive behavior of the synthesized azobenzene exhibited a photoresponse immediately after the on-off switching of blue light. The efficient cross-linking of azobenzene-bearing PEG through a click reaction allowed successful cell encapsulation in the azobenzene-bearing hydrogel. Taken together, the photoresponsive hydrogel scaffold is expected to find applications in controlling cellular behaviors in four dimensions via integrin-mediated mechanotransduction.

DOI: https://doi.org/10.1021/acsmacrolett.5c00549
ACS Biomater Sci Eng. 2025 Sep 17.

Real-Time Monitoring of the Formation and Culture of Hybrid Cell-Microbiomaterial Spheroids Using Non-Faradaic Electrical Impedance Spectroscopy.

Maria G Fois, Seppe Bormans, Thijs Vandenryt, Alexander P M Guttenplan, Yousra Alaoui Selsouli, Clemens van Blitterswijk, Zeinab Tahmasebi Birgani, Stefan Giselbrecht, Pamela Habibović, Ronald Thoelen, Roman K Truckenmüller.

  Cellular spheroids are considered a popular option for modeling healthy and diseased tissues in vitro and as injectable therapies. The formation and culture of spheroids can make use of different three-dimensional (3D) culture platforms, but the spheroids' analysis often has to rely on endpoint assays. In this study, we propose a microfluidic bioreactor to culture and nondestructively monitor human mesenchymal stem cell (hMSC) spheroids over time using non-Faradaic electr(ochem)ical impedance spectroscopy (EIS). For this, an array of porous microwells thermoformed from ion track-etched thin films and a pair of sensing electrodes from transparent indium tin oxide are integrated into the flow and culture chamber of the bioreactor. To measure the spheroid's electrical properties, the electrodes are connected to a frequency response analyzer (FRA), with a multiplexer in between to enable the operation of more than one bioreactor at the FRA at the same time. We find differences between the complex resistance/impedance and/or capacitance data of a reference condition without cells, a two-dimensional (2D) hMSC culture, hMSC spheroids, and hybrid spheroids aggregated from hMSCs and titanium or hydroxyapatite microparticles. We also found differences between different culture durations. These results suggest that our device can sense the presence and spatial arrangement of cells and micro(sized) biomaterials as a function of time.

Keywords:  micro(fluidic) bioreactors; microbiomaterials; microwell arrays; non-Faradaic electrical impedance spectroscopy; real-time monitoring; spheroids

DOI:  https://doi.org/10.1021/acsbiomaterials.5c00402