bims-ecemfi 2025-10-05 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2025–10–05
eleven papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Locked Nucleic Acid-Modified Force Probe Reveals High-Force Regulation of Yes-Associated Protein through Talin-Vinculin in Breast Cancer.
Modeling tumor transport and growth with poroelastic biopolymer networks.
Fiber recruitment drives a phase transition of cell polarization at a critical cell spacing in matrix-mediated tissue remodeling.
Dynamic hydrogel mechanics in organoid engineering: From matrix design to translational paradigms.
Rotational migration in human pancreatic ductal organoids depends on actin and myosin activity.
Biomimetic organo-hydrogels reveal the adipose tissue local mechanical anisotropy regulates ovarian cancer invasion.
Modeling of protein networks reveals factors affecting stiffness, yield stress, and strain stiffening in silk fibers.
Differential migration mechanics and immune responses of glioblastoma subtypes.
Synthetic Hydrogels Incorporating Hydrolytic/Nonhydrolytic Macromer Ratios Exhibit Improved Tunability of In Vivo Degradation and Immune Responses.
Microphysiological Systems of Lymphatics and Immune Organs.
Highly multiplexed 3D profiling of cell states and immune niches in human tumors.

ACS Nano. 2025 Oct 03.

Locked Nucleic Acid-Modified Force Probe Reveals High-Force Regulation of Yes-Associated Protein through Talin-Vinculin in Breast Cancer.

Tram Thi Hong Le, Jaehun Jung, Linh Thanh Nguyen, Min Ju Shon, Byoung Choul Kim.

  Integrins facilitate cellular mechanotransduction by transmitting mechanical cues from the extracellular matrix. While various DNA-based force probes have demonstrated integrin tension-dependent cellular responses, these typically measure forces up to ∼56 pN, limiting investigations of higher-force mechanobiological responses. Here, we develop a locked nucleic acid-based tension gauge tether (LNA-TGT) capable of measuring higher integrin tensions with increased stability compared to traditional DNA-based sensors. The LNA-TGT reveals that metastatic breast cancer cells exhibit a marked reduction in yes-associated protein (YAP) nuclear translocation under high-force conditions (approximately 60 pN). This effect correlates with a biphasic interaction between talin and vinculin at focal adhesions (FAs), which weakens at elevated tensions. Consequently, this leads to FA disassembly, actin fiber disruption, and diminished mechanical signaling to the nucleus. These findings suggest that LNA-TGTs provide a robust platform to probe high-force mechanotransduction, advancing our understanding of the relationship between integrin tension, cytoskeletal dynamics, and nuclear signaling in cells.

Keywords:  DNA-based force probe; LNA-modified DNA force probe; YAP translocation; cancer mechanobiology; tension gauge tether

DOI:  https://doi.org/10.1021/acsnano.5c13825
bioRxiv. 2025 Sep 25. pii: 2025.09.23.678021. [Epub ahead of print]

Modeling tumor transport and growth with poroelastic biopolymer networks.

Zecheng Li, Yifei Ren, Sharvari Kemkar, Paul Mollenkopf, Jakub Kochanowski, Paul A Janmey, Prashant K Purohit, Ravi Radhakrishnan, Kyle H Vining.

The mechanical properties of the extracellular matrix (ECM) regulate tumor growth and invasion in the tumor microenvironment. Models of biopolymer networks have been used to investigate the impact of elasticity and viscoelasticity of ECM on tumor behavior. Under tumor compression, these networks also show poroelastic behavior that is governed by the resistance to water flow through their pores. This work investigates the hypothesis that poroelastic properties regulate tumor growth. Here, alginate hydrogels with tunable ionic and hybrid ionic/covalent crosslinking are used as a model biopolymer system. Hydrogel stiffness, viscoelasticity, and stress relaxation behavior were characterized using stepwise axial compression. Among these properties, we find poroelastic fluid outflow dominates ECM stress relaxation, as the measured water flux was significantly affected under compression. Continuum mechanics-based modeling was developed to formulate and calculate the chemical potential gradients of water (solvent) in the hydrogels under compression. This framework was extended into an advection-diffusion framework to quantify growth factor (solute) distribution under varying strengths of stress and diffusion indexed by the relative strength of convective to diffusive transport, characterized by the Péclet number. An agent-based computational simulation showed that tumor growth was affected by Péclet number. Together, these results highlight the role of the poroelastic properties of ECM on water flux and transport in the tumor microenvironment.

DOI: https://doi.org/10.1101/2025.09.23.678021
Proc Natl Acad Sci U S A. 2025 Oct 07. 122(40): e2514995122

Fiber recruitment drives a phase transition of cell polarization at a critical cell spacing in matrix-mediated tissue remodeling.

Xiangjun Peng, Yuxuan Huang, Wenyu Kong, Yanan Du, Elliot L Elson, Xi-Qiao Feng, Guy M Genin.

  Biological tissues exhibit sharp phase transitions where cells collectively transition from disordered to ordered states at critical densities. We demonstrate through bio-chemo-mechanical modeling that this emergent behavior arises from a nonmonotonic dependence on nonlinear extracellular matrix (ECM) mechanics: mechanical communication between cells is optimized at intermediate stiffness values where cells can both generate sufficient forces and create strain-stiffened tension bands in the ECM. This balance establishes a critical cell spacing threshold for cell-cell communication ([Formula: see text]100 to 200 [Formula: see text]m) that is conserved across experimental observations for a broad range of cell types and collagen densities. Our model reveals that the critical stretch ratio at which fibrous networks transition from compliant to strain-stiffening governs this threshold through the formation of tension bands between neighboring cells. These mechanical communication networks drive collective phase transition in tissue condensation when cell density exceeds an effective percolation threshold. Our model explains how microscale cell-ECM interactions control emergent mechanical properties in biological systems and offers insight both into the physics of inhomogeneous materials under active stress, and into potential mechanical interventions for wound healing and fibrotic disorders.

Keywords:  cell–cell communication through fibrous ECM; mechanobiology; phase transitions; phenotypic transformation; tissue remodeling

DOI:  https://doi.org/10.1073/pnas.2514995122
Bioact Mater. 2026 Jan;55 144-170

Dynamic hydrogel mechanics in organoid engineering: From matrix design to translational paradigms.

Chenjia Zhang, Yue Shen, Mingyang Huang, Guoqing Wang, Qichen Miao, Heping Shi, Ruiqi Gao, Kun Wang, Ming Luo.

  The extracellular matrix (ECM) serves as a dynamic biomechanical regulator of cellular behavior, yet conventional 3D culture systems, such as Matrigel, lack the spatiotemporal control required to dissect mechanotransductive mechanisms in organoids. This review systematically explores the synthesis of mechanically tunable hydrogels-spanning stiffness and viscoelasticity-and their transformative applications in organoid research. By integrating natural, synthetic, and hybrid polymers, these hydrogels enable precise recapitulation of tissue-specific ECM mechanics, overcoming limitations of batch variability and static properties. We categorize hydrogel design strategies, emphasizing crosslinking paradigms (physical vs. chemical) and dynamic bond engineering, which permit real-time modulation of mechanical cues. Applications across developmental organoids (intestinal, hepatic, renal, neural) reveal stiffness-dependent morphogenesis, where optimal mechanical niches enhance maturation via YAP/Notch signaling. Tumor organoid models (breast, pancreatic, colorectal) further demonstrate how matrix stiffening drives malignancy through mechanosensitive pathways, such as epithelial-mesenchymal transition and drug resistance. Emerging viscoelastic hydrogels, tailored via alginate molecular weight or decellularized ECM, replicate dynamic tissue mechanics, advancing cartilage and cerebellar organoid models. Critically, this review highlights innovations in programmable hydrogels that bridge 2D reductionist models and in vivo complexity, offering unprecedented insights into ECM-driven organogenesis and disease progression. Future directions include integrating bioprinting and organ-on-a-chip technologies to achieve vascularized, patient-specific organoids. By synthesizing design principles and mechanobiological mechanisms, this work establishes a roadmap for next-generation biomaterials, accelerating translational applications in drug screening, regenerative medicine, and personalized oncology.

Keywords:  Extracellular matrix; Mechanically controlled hydrogel; Organoid; Stiffness; Viscoelasticity

DOI:  https://doi.org/10.1016/j.bioactmat.2025.09.021
bioRxiv. 2025 Sep 24. pii: 2024.10.01.616188. [Epub ahead of print]

Rotational migration in human pancreatic ductal organoids depends on actin and myosin activity.

Gengqiang Xie, Chaity Modak, Olalekan H Usman, Raphael Wf Tan, Nicole Coca, Gabriela De Jesus, Yue Julia Wang, D Thirumalai, Xin Li, Jerome Irianto.

Rotational migration is one specific form of collective cell migration when epithelial cells are confined in a spherical geometry, such as in the epithelial acini. This tissue-level rotation motion is crucial for the morphogenesis of multiple epithelial systems. Here, we introduce a new primary human model for the study of rotational migration, pancreatic ductal organoids. Live imaging revealed the persistent rotation of the organoids over time. By tracking the nuclei, the three-dimensional trajectory of the cellular movement was reconstructed and the velocity of the rotation was quantified. The presence of focal adhesion clusters and prominent actin stress fibers were observed at the basal side of the organoids, suggesting the interactions between the cells and the surrounding extracellular matrix. Finally, our inhibition study showed the dependence of pancreatic ductal organoid rotational migration on myosin activity, actin polymerization, and actin branching. We hope that this model will enable future studies with human primary cells, which are more faithful to normal epithelial cells.

DOI: https://doi.org/10.1101/2024.10.01.616188
Nat Commun. 2025 Sep 29. 16(1): 8541

Biomimetic organo-hydrogels reveal the adipose tissue local mechanical anisotropy regulates ovarian cancer invasion.

Jordi Gonzalez-Molina, Parisa Nabili, Daniele Marciano, Sara Abdelnabi, Okan Gultekin, Mohammed Fatih Rasul, Yikun Zhang, Clémence Nadal, Alexandra Chrysanthou, Twana Alkasalias, Sahar Salehi, Frances Balkwill, Kaisa Lehti, Julien E Gautrot.

High-grade serous ovarian cancer, the most common and aggressive ovarian cancer subtype, frequently metastasises to visceral adipose tissues. In these tissues, the extracellular matrix through which ovarian cancer cells migrate is constrained by the presence and preponderance of adipocytes. How cells migrate in this unique environment is not known, yet critical to understanding metastatic progression. To study these processes, we developed biomimetic organo-hydrogels that recreate structural, mechanical, and biochemical properties of human adipose tissues. We show that ovarian cancer cells present invasive tropism towards organo-hydrogels, replicating the behaviour observed in native adipose tissues. This migration is facilitated by the mechanical anisotropy and microstructure of organo-hydrogels and adipose tissues, allowing the formation of migratory tracks. These results highlight the contribution of adipocytes to tissue biophysical features as a key regulatory factor of ovarian cancer cell migration and demonstrate that organo-hydrogels are particularly relevant tools to develop in vitro models of complex tissue architectures with high cellularity.

DOI: https://doi.org/10.1038/s41467-025-62296-7
Acta Biomater. 2025 Sep 30. pii: S1742-7061(25)00703-2. [Epub ahead of print]

Modeling of protein networks reveals factors affecting stiffness, yield stress, and strain stiffening in silk fibers.

Noy Cohen, Fuzhong Zhang.

  Thanks to their high stiffness, tensile strength, and toughness, silk fibers generated significant interest and are being considered for many applications. The superior properties of these fibers stem from a unique microstructure, which comprises crystalline domains and polypeptide chains that interact through weak intermolecular interactions. Recent works show that these fibers can be engineered to achieve target mechanical properties and response. Specifically, the uniaxial stretching of silk fibers typically results in a linear response up to a yield point, after which the fiber can exhibit a plateau or strain stiffening up to failure. The response depends on the amino-acid sequence and the molecular weights (MWs) of the peptides, which determine the degree of crystallinity in the network. In this work, we employ statistical mechanics to develop a microscopically motivated framework that sheds light on the underlying mechanisms that govern the fiber response. We propose that upon the application of a tensile force, the linear deformation is enabled by the distortion of weak intermolecular interactions, up to their rupture at a yield stress. In fibers with low crystallinity, the chains are not interconnected and therefore carry minimal load due to potential weak intramolecular interactions, resulting in a plateau stress up to failure. In fibers with a high degree of crystallinity, the crystalline domains are stiff and therefore deformations are enabled through the entropic stretching of the chains in the amorphous region, leading to strain stiffening. Our framework is validated through a comparison to two sets of experiments: (1) fibers with the same MWs but different sequences and (2) fibers with the same sequence but different MWs. The findings from this work enable to compare between the microstructures of different protein-based fibers and pave the way to the design of novel fibers with target mechanical properties and response.

Keywords:  Mechanical properties of fibers; Multi-scale modeling; Protein fibers; Silk fibers

DOI:  https://doi.org/10.1016/j.actbio.2025.09.036
bioRxiv. 2025 Sep 22. pii: 2022.06.26.497270. [Epub ahead of print]

Differential migration mechanics and immune responses of glioblastoma subtypes.

Ghaidan A Shamsan, Chao J Liu, Brooke C Braman, Ruyi Li, Susan K Rathe, Aaron L Sarver, Nima Ghaderi, Mariah M McMahon, Rebecca L Klank, Barbara R Tschida, S Joey McFarren, Pamela C Rosato, David Masopust, Jann N Sarkaria, H Brent Clark, Steven S Rosenfeld, David A Largaespada, David J Odde.

Glioblastoma remains a deadly cancer driven in part by invasion of tumor cells into the brain. Transcriptomic analyses have identified distinct molecular subtypes, but mechanistic differences that account for clinical differences are not clear. Here, we show that, as predicted by the motor-clutch model of cell migration, mesenchymal glioma cells are more spread, generate larger traction forces, and migrate faster in brain tissue compared to proneural cells. Despite their rapid migration and comparable proliferation rates in vitro, mice with mesenchymal tumors survive longer than those with proneural tumors. This improved survival correlated with an immune response in the mesenchymal tumors, including T cell-mediated. Consistently, inducing mesenchymal tumors in immunodeficient mice resulted in shorter survival supporting a protective immune role in mesenchymal tumors. Thus, mesenchymal tumors have aggressive migration, but are immunologically hot which suppresses net proliferation. These two features counteract each other and may explain the lack of a strong survival difference between subtypes clinically, while also opening up new opportunities for subtype-specific therapies.

DOI: https://doi.org/10.1101/2022.06.26.497270
Adv Healthc Mater. 2025 Oct 01. e02475

Synthetic Hydrogels Incorporating Hydrolytic/Nonhydrolytic Macromer Ratios Exhibit Improved Tunability of In Vivo Degradation and Immune Responses.

Michael D Hunckler, Sophia Kioulaphides, Karen E Martin, Angelica L Torres, Graham F Barber, Stephen W Linderman, Rebecca S Schneider, Andrés J García.

  Proteolytically degradable hydrogels are widely used as delivery carriers in regenerative medicine. However, the in vivo degradation rate of these materials is difficult to control because of site-specific enzymatic activity, implant design, and disease state, impairing tissue regeneration. Hydrogels with crosslinks that degrade hydrolytically offer an alternate route to tune in vivo degradation profile. In this study, a synthetic 4-arm maleimide-terminated poly(ethylene glycol) (PEG-4MAL) hydrogel system that combines hydrolytic ester-linked PEG-4MAL (PEG-4eMAL) macromer with nondegradable amide-linked PEG-4MAL (PEG-4aMAL) macromer in various stoichiometric ratios to tune the degradability rate is engineered. The macromers are crosslinked with dithiothreitol (DTT) via thiol-maleimide click reaction. Rheological analysis shows that a family of PEG-4eMAL/PEG-4aMAL hydrogels has equivalent mechanical properties, but increasing the PEG-4eMAL content increases the rate of degradation in vitro and in vivo. PEG-4eMAL/PEG-4aMAL hydrogels support high viability of encapsulated human cells. Notably, the ratio of PEG-4eMAL/PEG-4aMAL modulates local immune cell recruitment when implanted in the subcutaneous space. These results establish the use of PEG-4eMAL/PEG-4aMAL hydrogels as a hydrolytically degradable platform to tune in vivo degradation and immune responses.

Keywords:  hydrogels; hydrolytic degradability; poly(ethylene glycol); tunability

DOI:  https://doi.org/10.1002/adhm.202502475
Adv Healthc Mater. 2025 Sep 29. e03201

Microphysiological Systems of Lymphatics and Immune Organs.

Ishita Jain, Ankur Singh, Andrés J García.

  Microphysiological systems (MPS) that incorporate engineered blood vasculatures have enabled new opportunities to study human physiology and disease, offering platforms for drug development, tissue modeling, and regenerative medicine. However, most human tissues also contain an equally complex yet underrepresented secondary vascular network, the lymphatic system. Lymphatics play indispensable roles in interstitial fluid drainage, immune cell trafficking, and antigen presentation, and are central to the pathophysiology of diseases such as lymphedema, chronic inflammation, and cancer metastasis. Despite their critical biological functions, lymphatic vessels and associated immune structures, such as lymph nodes, remain absent from current in vitro models. Integrating lymphatics into biomaterials-based MPS is essential for capturing the dynamic interplay between fluid transport, immune surveillance, and tissue homeostasis. This review surveys recent progress in engineering lymphatic microenvironments and immune organoids within biomaterials-based MPS, emphasizing innovative strategies to recreate the biochemical and biophysical complexity of native lymphatic tissues. Advances are highlighted in tunable extracellular matrix platforms, humanized cell sourcing, and precision fabrication techniques, including perfusable, modular, and scalable models. The integration of lymphatic components with multi-organ systems, combined with the application of computational modeling and machine learning, offers unprecedented opportunities to build personalized and physiologically relevant immune models. Incorporating lymphatics into next-generation MPS promises to illuminate fundamental disease mechanisms and accelerate the development of more predictive therapeutic testing platforms with improved clinical translation.

Keywords:  hydrogels; lymph node; lymphadema; lymphatics; organ‐on‐chip

DOI:  https://doi.org/10.1002/adhm.202503201
Nat Methods. 2025 Sep 29.

Highly multiplexed 3D profiling of cell states and immune niches in human tumors.

Clarence Yapp, Ajit J Nirmal, Felix Zhou, Alex Y H Wong, Juliann B Tefft, Yi Daniel Lu, Zhiguo Shang, Zoltan Maliga, Paula Montero Llopis, George F Murphy, Christine G Lian, Gaudenz Danuser, Sandro Santagata, Peter K Sorger.

Diseases such as cancer involve alterations in cell proportions, states and interactions, as well as complex changes in tissue morphology and architecture. Histopathological diagnosis of disease and most multiplexed spatial profiling relies on inspecting thin (4-5 µm) specimens. Here we describe a high-plex cyclic immunofluorescence method for three-dimensional tissue imaging and use it to show that few, if any, cells are intact in conventional thin tissue sections, reducing the accuracy of cell phenotyping and interaction analysis. However, three-dimensional cyclic immunofluorescence of sections eightfold to tenfold thicker enables accurate morphological assessment of diverse protein markers in intact tumor, immune and stromal cells. Moreover, the high resolution of this confocal approach generates images of cells in a preserved tissue environment at a level of detail previously limited to cell culture. Precise imaging of cell membranes also makes it possible to detect and map cell-cell contacts and juxtracrine signaling complexes in immune cell niches.

DOI: https://doi.org/10.1038/s41592-025-02824-x