bims-ecemfi Biomed News
on ECM and fibroblasts
Issue of 2025–06–29
thirteen papers selected by
Badri Narayanan Narasimhan, University of California, San Diego
  1. Confinement Suppresses Mechanical Force-Mediated Cancer Cell Apoptosis.
  2. A multiscale theory for mesenchymal cell migration in straight or curved channel confinement.
  3. Reinforcement of Fibrillar Collagen Hydrogels with Bioorthogonal Covalent Crosslinks.
  4. Consolidation of cell-ECM adhesion through direct talin-mediated actin linkage is essential for mouse embryonic morphogenesis.
  5. Geometrically Controlled WNT Activation Drives Intestinal Morphogenesis.
  6. Cytoplasmic anillin and Ect2 promote RhoA/myosin II-dependent confined migration and invasion.
  7. A model for contractile stress fibers embedded in bulk actomyosin networks.
  8. Interfacial Stress Regulates Plasticity and Drug Resistance at the Breast Cancer-Host Interface.
  9. Elucidating Mechanisms of Gelation, Fiber Assembly, and Stability of Injectable Decellularized Extracellular Matrix Biomaterials.
  10. A Dock8-dependent mechanosensitive central actin pool maintains T cell shape and protects nucleus during migration.
  11. Apical size reduction by macropinocytosis alleviates tissue crowding.
  12. External strain on the plasma membrane is relayed to the endoplasmic reticulum by membrane contact sites and alters cellular energetics.
  13. Tuneable Hydrogel Porosity via Dynamic Tailoring of Spinodal Decomposition.
  1. Small. 2025 Jun 25. e2504261
    Confinement Suppresses Mechanical Force-Mediated Cancer Cell Apoptosis.
    Alka Kumari, Akshay Kumar, Gao Xu, Kaustav Roy, Rudra Pratap, Andrew Holle, Ajay Tijore.
      During the invasion, cancer cells migrate through '3D channel-like tracks' present in the tissues' interstitial extracellular matrix (ECM). Cancer cell migration through these 3D confined channels leads to confinement-induced cell deformation. Emerging reports show that cancer cells are susceptible to mechanical stretch/ultrasound (US)-mediated mechanical forces and undergo calcium-dependent apoptosis (mechanoptosis) under conditions that promote normal cell growth. Surprisingly, we find that confinement-induced cell deformation suppresses mechanoptosis. Studies done using microchannel platforms and tumor spheroid models show that a low level of apoptosis is observed in confined cells. Further, apoptosis level is found to increase with a decrease in the degree of confinement. The absence of mature focal adhesions (FAs), low myosin IIA contractility, and diffuse mechanosensitive Piezo1 channels are responsible for a low level of apoptosis in confined cells. Thus, these findings suggest that confined cells, due to the absence of mature FAs, could not sense and transduce the mechanical forces and generate enough myosin IIA contractility required to initiate apoptosis. The combined action of US and activators of myosin contractility can be used to target invading cancer cells.
    Keywords:  apoptosis; confinement; low‐frequency ultrasound; mechanotransduction; piezo1
    DOI:  https://doi.org/10.1002/smll.202504261
  2. Biophys J. 2025 Jun 24. pii: S0006-3495(25)00380-7. [Epub ahead of print]
    A multiscale theory for mesenchymal cell migration in straight or curved channel confinement.
    Wenya Shu, C Nadir Kaplan.
      Mesenchymal cells navigate the extracellular matrix (ECM) in vivo by processing both its mechanical properties and confinement geometry. Here we develop a multiscale whole-cell theory to investigate cell spreading and migration in two-dimensional (2D) viscoelastic channel confinements of varying width and curvature. Our simulations show that, in straight channels, the cell migration speed depends monotonically on the substrate elastic stiffness, which is otherwise biphasic on an unconfined substrate. This is because confinement enforces directional spreading while reducing the spreading area, which results in lower intracellular viscous drag on the nucleus and a higher net traction force of polarized cells in our model. In contrast, we find that confinement curvature slows down cell migration since the friction forces between the bending cell and the confinement walls increase with curvature. We validate our model with experimental data for cell migration in straight channels spanning a wide range of the ECM stiffness as well as in curved channels. Our model illuminates the intertwined effects of substrate viscoelasticity and confinement geometry on cell spreading and migration in complex microenvironments, revealing that channel curvature can hierarchically override substrate mechanics to dominate migration regulation. The study paves the way for designing scaffolds that leverage curvature and confinement to steer controllable cell migration.
    Keywords:  Channel; Confinement; Curvature; Mechanobiology; Viscoelasticity
    DOI:  https://doi.org/10.1016/j.bpj.2025.06.020
  3. Biomacromolecules. 2025 Jun 24.
    Reinforcement of Fibrillar Collagen Hydrogels with Bioorthogonal Covalent Crosslinks.
    Lucia G Brunel, Chris M Long, Fotis Christakopoulos, Betty Cai, Narelli de Paiva Narciso, Patrik K Johansson, Diya Singhal, Neil J Baugh, Daiyao Zhang, Annika Enejder, David Myung, Sarah C Heilshorn.
      Bioorthogonal covalent crosslinking stabilizes collagen type I hydrogels, improving their structural integrity for tissue engineering applications with encapsulated living cells. The chemical modification required for crosslinking, however, interferes with the fibrillar nature of the collagen, leading instead to an amorphous network without fibers. We demonstrate an approach to perform bioconjugation chemistry on collagen with controlled localization such that the modified collagen retains its ability to self-assemble into a fibrillar network while also displaying functional groups for covalent crosslinking with bioorthogonal click chemistry. The collagen matrix is formed through a sequential crosslinking process, in which the modified collagen first physically assembles into fibers and then is covalently crosslinked. This approach preserves the fibrous architecture of the collagen, guiding the behavior of encapsulated human corneal mesenchymal stromal cells while also reinforcing fibers through covalent crosslinks, strengthening the stability of the cell-laden collagen hydrogel against cell-induced contraction and enzymatic degradation.
    DOI:  https://doi.org/10.1021/acs.biomac.5c00398
  4. Commun Biol. 2025 Jun 21. 8(1): 948
    Consolidation of cell-ECM adhesion through direct talin-mediated actin linkage is essential for mouse embryonic morphogenesis.
    Wenjun Deng, Rosalyn L Carr, Rhea R Kaul, Marina Pavlova-Deb, Amanda Haage, Pere Roca-Cusachs, Guy Tanentzapf.
      During animal development, cell-ECM adhesion mediated by integrins is required for the assembly and maintenance of tissues and organs. It can either be transient or stable and requires linking integrins to the cytoskeleton. Talin can link integrins to actin either directly through its actin-binding sites (ABSs) or indirectly by recruiting downstream actin-binding molecules. In Drosophila, talin's ABS3 domain is essential for biological functions, but its role remains unknown in mammalian systems. Here, we investigate the role of direct talin-mediated actin linkage in mammals by generating a mouse model containing point mutations in talin's ABS3 domain. We find that mutant mice exhibit early developmental defects and die midway through embryogenesis. Primary mouse embryonic fibroblasts generated from mutants form prominent focal adhesions but show defective consolidation and maturation. Adhesion dynamics, cell spreading, actin dynamics and organization, and traction force generation are also impacted in mutants, which affect processes such as cell migration that impinge on multiple events during early mouse embryogenesis. Overall, our work provides key mechanistic insights into how direct coupling of ECM to actin through talin has specific and critical roles in controlling adhesion dynamics required for early mammalian development.
    DOI:  https://doi.org/10.1038/s42003-025-08294-3
  5. Adv Healthc Mater. 2025 Jun 23. e2502832
    Geometrically Controlled WNT Activation Drives Intestinal Morphogenesis.
    Nathaniel C Burmas, Arlyn M Fabian, Amoli Vanavadiya, Quinton Smith.
      Morphogenesis is a multifaceted process that integrates biochemical signals with mechanical and architectural cues to drive tissue formation. Here, the modulation of WNT signaling and engineered microenvironments synergistically drive crypt-villus-like morphogenesis in colorectal carcinoma (Caco-2) cells. Fibroblast conditioned media induced WNT-dependent budding, confirmed via secretome profiling and WNT inhibition by Dickkopf-1 (DKK1). Direct modulation of WNT activity with agonist CHIR enhanced both epithelial budding and mucin 2 (MUC2) expression. To isolate the role of architecture in this process, fabricated gelatin methacrylate (GelMA) microwell arrays via digital light processing (DLP) printing enabled independent control of geometry and stiffness. Increased scaffold perimeter-to-area ratios promoted epithelial budding and MUC2 upregulation, even in the absence of exogenous WNT agonists. Disruption of myosin contractility abolished these effects, underscoring the importance of mechanotransduction in this process. These findings reveal that mechanical and architectural cues can independently orchestrate intestinal epithelial morphogenesis, offering new strategies for gut-mimetic culture systems.
    Keywords:  bioprinting; intestine; mechanotransduction; morphogenesis; tissue engineering
    DOI:  https://doi.org/10.1002/adhm.202502832
  6. Nat Mater. 2025 Jun 26.
    Cytoplasmic anillin and Ect2 promote RhoA/myosin II-dependent confined migration and invasion.
    Avery T Tran, Emily O Wisniewski, Panagiotis Mistriotis, Konstantin Stoletov, Maria Parlani, Alice Amitrano, Brent Ifemembi, Se Jong Lee, Kaustav Bera, Yuqi Zhang, Soontorn Tuntithavornwat, Alexandros Afthinos, Alexander Kiepas, Bhawana Agarwal, Sanjiban Nath, John J Jamieson, Yi Zuo, Daniel Habib, Pei-Hsun Wu, Stuart S Martin, Sharon Gerecht, Luo Gu, John D Lewis, Petr Kalab, Peter Friedl, Konstantinos Konstantopoulos.
      Cell migration in mechanically confined environments is a crucial step of metastatic cancer progression. Nonetheless, the molecular components and processes mediating such behaviour are still not fully understood. Here we demonstrate that a pool of the scaffolding protein anillin and its cofactor Ect2, which are both predominantly nuclear proteins and critical mediators of cytokinesis, is present in the cytoplasm of multiple interphase cell types that promote confined cell migration. Confined migration in biomimetic microfluidic models triggers the actomyosin-binding-dependent recruitment of anillin to the plasma membrane at the poles of migrating cells in a manner that scales with microenvironmental stiffness and confinement. The guanine nucleotide exchange activity of Ect2 is required for its RhoA-GTPase-mediated activation of myosin II at the cell poles, enhancing invasion, bleb-based migration and extravasation. Confinement-induced nuclear envelope rupture further amplifies this process due to the release of further anillin and Ect2 into the cytoplasm. Overall, these results show how Ect2 and anillin cooperate to mediate RhoA/ROCK/myosin II-dependent mechanoadaptation and invasive cancer progression.
    DOI:  https://doi.org/10.1038/s41563-025-02269-9
  7. J Math Biol. 2025 Jun 26. 91(2): 14
    A model for contractile stress fibers embedded in bulk actomyosin networks.
    Mariya Savinov, Charles S Peskin, Alex Mogilner.
      Contractile cytoskeletal structures such as fine actomyosin meshworks and stress fibers are essential force-generators for mechanical phenomena in live cells, including motility, morphogenesis, and mechanosensing. While there have been many studies on the rheology and assembly of individual stress fibers, few mathematical models have explicitly modeled the bulk actomyosin network in which stress fibers are embedded, particularly not in the case of high actin turnover. Generally the extent of the interplay between embedded stress fibers and contractile bulk networks is still not well understood. To address this gap, we design a model of stress fibers embedded in bulk actomyosin networks which utilizes the immersed boundary method, allowing one to consider various stress fiber rheologies in the context of an approximately viscous, compressible, contractile bulk network. We characterize the dynamics of bulk actomyosin networks with and without embedded stress fibers, and simulate a laser ablation experiment to demonstrate the effective long-range interactions between stress fibers as well as how perturbations of stress fibers can result in symmetry breaking of the bulk actomyosin network. This paper is a part of the Special Collection "Problems, Progress and Perspectives in Mathematical and Computational Biology".
    Keywords:  Actomyosin; Cytoskeleton; Fluid–structure interaction; Immersed boundary method; Mechanical modeling
    DOI:  https://doi.org/10.1007/s00285-025-02245-6
  8. Adv Sci (Weinh). 2025 Jun 26. e09361
    Interfacial Stress Regulates Plasticity and Drug Resistance at the Breast Cancer-Host Interface.
    Bram G Soliman, Peilin Tian, Jiuyu Cui, Kristopher A Kilian, J Justin Gooding.
      The confinement of breast cancer cells at the interface of the mammary gland lumen and its surrounding extracellular matrix is thought to be a key physical driver of cellular plasticity. The relationship between confinement-induced solid stress and drug resistance is not well understood due to a scarcity of models that faithfully isolate the contribution of confinement on cancer cell behavior. Herein, drop-on-demand printing is used to uniquely replicate the spatial compartmentalization of the native cancer-host interface: MCF-7 breast cancer cells are dispensed within bioinert cup-shaped alginate-based hydrogels in high-throughput to yield "confined" spheroids. Hydrogel confinement affects the emergence of CD44+-CD133+ cells at the spheroid interface that drives a two-fold increase in doxorubicin/tamoxifen resistance compared to control "unconfined" spheroids. Whilst the peripheral drug-resistant phenotype is observed clinically, the model is unique in facilitating the emergence of this population in an in vitro setting. Pharmacological modulation of mechanotransduction proteins (YAP, myosin), abrogated the emergence of this peripheral phenotype, implicating mechanotransduction pathways as an effective way to target solid stress-induced drug resistance. Together, this supports an "interfacial stress-stemness-drug resistance" relationship that sheds new light on the existing paradigm of spatial emergence of drug resistance in breast cancer.
    Keywords:  cancer; cellular heterogeneity; confinement; drop‐on‐demand printing; drug delivery; drug resistance; solid stress
    DOI:  https://doi.org/10.1002/advs.202509361
  9. Biopolymers. 2025 Jul;116(4): e70037
    Elucidating Mechanisms of Gelation, Fiber Assembly, and Stability of Injectable Decellularized Extracellular Matrix Biomaterials.
    Alexander Chen, Michael B Nguyen, Julian Cheng, Benjamin D Bridgelal, Kate E Reimold, Joshua Tesoro, Estefania Encisco-Pelayo, Karen L Christman.
      Decellularized extracellular matrix (dECM)-based biomaterials have been widely used for their applications in tissue engineering. In particular, pepsin digestion of dECM can be used to generate injectable forms, including ECM hydrogels as well as an intravascularly infusible ECM (iECM). However, fundamental materials characterization of these materials has been limited, and thus little is known about what exactly drives gelation of ECM hydrogels or the conditions for fibril assembly and growth. With this study, we sought to answer a fundamental question on how these materials assemble or gel, as well as a translational question on what storage conditions are suitable for these materials. Here, we used second-harmonic generation and transmission electron microscopy to investigate the mechanism of gelation for ECM hydrogels and the nanofibril assembly of the iECM. Overall, these microscopies revealed the origin and morphology of self-assembly and that type I collagen lateral and longitudinal growth drives ECM hydrogel formation. On the contrary, the iECM preserved the same mechanism for nanofiber assembly without gelation. In terms of translation, ensuring the stability after rehydration is critical for therapeutic injection timing since changes in the material could impact both safety and efficacy. Via microscopy in conjunction with bulk material characterization, we found that dECM formulations are best kept at 4°C for a maximum of 24 h after rehydration in order to maintain their original properties. Overall, this work provides evidence for the type I collagen directed self-assembly within heterogeneous, injectable, decellularized ECM biomaterials and also determines clinically relevant material storage conditions.
    Keywords:  decellularized extracellular matrix; hydrogel; intravascular; self‐assembly
    DOI:  https://doi.org/10.1002/bip.70037
  10. Sci Immunol. 2025 Jun 26. eadt9239
    A Dock8-dependent mechanosensitive central actin pool maintains T cell shape and protects nucleus during migration.
    Connie Shen, Aysha Cerf, Jérémy Postat, Aanya Bhagrath, Mauricio Merino, Angela Mingarelli, Grace Barnes, Dhanesh Patel, Dakota Rogers, Vincent M Luo, Afnan Abu-Thuraia, Caitlin Schneider, Daniela F Quail, Abhinav Sharma, Woong-Kyung Suh, Allen Ehrlicher, Jean-François Côté, Judith N Mandl.
      Immune cells navigate through complex tissue architectures by extensive cellular deformation, low adhesion, and high cell velocities. Loss-of-function mutations in Dedicator of Cytokinesis 8 (Dock8) are associated with immunodeficiency as immune cells becoming entangled during migration through dense environments, but their migration on two-dimensional surfaces remains entirely intact. Here we investigated the specific cytoskeletal defect of Dock8-deficient activated T cells and describe a central pool of F-actin in wild-type murine and human T cells that is absent in Dock8 knockout T cells. The appearance of the central actin pool is mechanoresponsive and emerges only when cells are very confined. We identified mammalian sterile 20-like (Mst1) as a necessary component in this mechanosensitive pathway in addition to Dock8, allowing for cell shape integrity and survival during migration through complex environments. Our work shows that loss of the central actin pool results in greater nuclear deformation, accrual of DNA damage, and premature cell senescence.
    DOI:  https://doi.org/10.1126/sciimmunol.adt9239
  11. Nat Commun. 2025 Jun 23. 16(1): 5338
    Apical size reduction by macropinocytosis alleviates tissue crowding.
    Enzo Bresteau, Eve E Suva, Christopher Revell, Osama A Hassan, Aline Grata, Jennifer Sheridan, Jennifer Mitchell, Constadina Arvanitis, Farida Korobova, Sarah Woolner, Oliver E Jensen, Brian Mitchell.
      Tissue crowding represents a critical challenge to epithelial tissues, which often respond via the irreversible process of live cell extrusion. We report that apical size reduction via macropinocytosis serves as a malleable and less destructive form of tissue remodeling that can alleviate the need for cell loss. We find that macropinocytosis is triggered by tissue crowding via mechanosensory signaling, leading to substantial internalization of apical membrane. This drives a reduction in apical surface which alleviates crowding. We report that this mechanism regulates the long-term organization of the developing epithelium and controls the timing of proliferation-induced cell extrusion. Additionally, we observe a wave of macropinocytosis in response to acute external compression. In both scenarios, inhibiting macropinocytosis induces a dramatic increase in cell extrusion suggesting cooperation between cell extrusion and macropinocytosis in response to both developmental and external compression. Our findings implicate macropinocytosis as an important regulator of dynamic epithelial remodeling.
    DOI:  https://doi.org/10.1038/s41467-025-60724-2
  12. Sci Adv. 2025 Jun 27. 11(26): eads6132
    External strain on the plasma membrane is relayed to the endoplasmic reticulum by membrane contact sites and alters cellular energetics.
    Ziming Chen, Peilin Chen, Jiayue Li, Euphemie Landao-Bassonga, John Papadimitriou, Junjie Gao, Delin Liu, Andrew Tai, Jinjin Ma, David Lloyd, Brendan F Kennedy, Ming Hao Zheng.
      Mechanotransduction is essential for living cells to adapt to their extracellular environment. However, it is unclear how the biophysical adaptation of intracellular organelles responds to mechanical stress or how these adaptive changes affect cellular homeostasis. Here, using the tendon cell as a mechanosensitive cell type within a bioreactor, we show that the tension of the plasma membrane (PM) and the endoplasmic reticulum (ER) adaptively increases in response to repetitive external stimuli. Depletion of stromal interaction molecule 1 (STIM1), the highest expressed PM-ER tether protein, interfered with mechanotransduction from the PM to the ER, and affected the ER tension. We found that an optimized mechanical strain increased ER tension in a homeostatic manner, but excessive strain resulted in ER expansion, as well as activating ER stress. Last, we showed that changes in ER tension were linked with ER-mitochondria interactions and associated with cellular energetics and function. Together, these findings identify a PM-ER mechanotransduction mechanism that dose-dependently regulates cellular metabolism.
    DOI:  https://doi.org/10.1126/sciadv.ads6132
  13. Adv Sci (Weinh). 2025 Jun 26. e04265
    Tuneable Hydrogel Porosity via Dynamic Tailoring of Spinodal Decomposition.
    Michael Halwes, Callum Vidler, Lilith Caballero Aguilar, Farzaneh Taromian, David R Nisbet, Melanie Stamp, Khoon S Lim, Andrea J O'Connor, David J Collins.
      Pores within hydrogel structures play a crucial role in fostering cell growth and tissue development. The creation and control of pore size and interconnectivity can be conveniently achieved with aqueous two-phase emulsions. The decomposition of these emulsions into two separate phases can be controlled by carefully choosing the polymer components and solution conditions. Spinodal decomposition, a mechanism of phase separation, can result in a highly interconnected pore morphology, though controlling this process is difficult in practice, limiting its application for in vitro models. Here, a straightforward method is introduced for dynamically halting the phase separation of a gelatin methacryloyl and poly(vinyl alcohol) (GelMA-PVA) polymer blend in the context of a biofabrication process based on dynamic interface printing (DIP). This is enabled by a novel approach based on the concerted application of acoustic mixing and photocuring to structure the pore size, orientation, and interconnectivity in hydrogels. This approach accordingly enables spatially addressable fabrication of 3D hydrogel architectures, with the potential to enhance the functionality of engineered tissues via tailored microenvironments.
    Keywords:  GelMA; bioprinting; dynamic interface printing; porous hydrogel; spinodal decomposition
    DOI:  https://doi.org/10.1002/advs.202504265
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