bims-ecemfi Biomed News
on ECM and fibroblasts
Issue of 2025–09–07
thirteen papers selected by
Badri Narayanan Narasimhan, University of California, San Diego
  1. Human progenitor T-cell differentiation regulated by the mechanical resistance of thymus-mimetic extracellular matrices.
  2. Local photocrosslinking of native tissue matrix regulates lung epithelial cell mechanosensing and function.
  3. Controlling Intestinal Organoid Polarity using Synthetic Dynamic Hydrogels Decorated with Laminin-Derived IKVAV Peptides.
  4. Dynamic Macropore Formation via Dual-Degrading Injectable Microgels Enhances Host-Mediated Angiogenesis and Regeneration.
  5. Dynamic and atypical E-cadherin-based attachments mediate melanoblast migration through confined epithelial spaces.
  6. Mechanical interactions impact the functions of immune cells and their application in immunoengineering.
  7. Compression causes cancer cells to start spreading.
  8. Epithelial tension controls intestinal cell extrusion.
  9. Enhanced Mechanophore Activation in Hydrogel Networks Driven by Swollen Network Pretension.
  10. Physical confinement and phagocytic uptake induce persistent cell migration.
  11. Curved Magnetic Hydrogels for Understanding Cancer Initiation.
  12. Bioassembly of Myoblast Spheroids in Electrofibrillated Scaffolds for 3D Muscle Tissue Biofabrication.
  13. 3D printed anisotropic tissue simulants with embedded fluid capsules for medical simulation and training.
  1. bioRxiv. 2025 Aug 27. pii: 2025.08.27.671384. [Epub ahead of print]
    Human progenitor T-cell differentiation regulated by the mechanical resistance of thymus-mimetic extracellular matrices.
    Nicholas Jeffreys, Kyle T Ruark, Joshua M Price, Ella M Serrano-Wu, Blake Hanan, Andrew S Khalil, Wei-Hung Jung, Nuria Lafuente-Gómez, Joshua M Brockman, Andrew Lu, Izabela Zmirska, Kyle H Vining, Junzhe Lou, Kwasi Adu-Berchie, Siyoon Kwon, Hamza Ijaz, Azeem Sharda, David T Scadden, David J Mooney.
      Therapeutic T-cell engineering ex vivo from human hematopoietic stem cells (HSCs) focuses on recapitulating notch1-signaling and α4β1-integrin-mediated adhesion within the thymic niche with supportive stromal cell feeder-layers or surface-immobilized recombinant protein-based engineered thymic niches (ETNs). The relevant Notch1-DLL-4 and α4β1-integrin-VCAM-1 interactions are known to respond to mechanical forces that regulate their bond dissociation behaviors and downstream signal transduction, yet manipulating the mechanosensitive features of these key receptor-ligand interactions in thymopoiesis has been largely ignored in current ETN designs. Here, we demonstrate that human T-cell development from cord blood-derived CD34 + HSCs is regulated via molecular cooperativity in notch1 and integrin-mediated mechanotransduction. Mechanically confining interpenetrating network (IPN) hydrogel-based 3D cell culture comprised of collagen type I and alginate polysaccharides functionalized with DLL-4 and VCAM-1 is used as a model viscoelastic 3D ETN to manipulate human progenitor (pro)T-cell differentiation. This ETN enables orthogonal control of the mechanical and biomolecular features of the thymic niche, including thymopoietic ligand density, modulus, and viscoelastic properties (e.g., stress relaxation kinetics). We identify that soft, viscous matrices that enhance activation of the notch1-pathway, and subsequently notch1 intracellular domain (NICD) nuclear import sustain the T-cell development gene regulatory network during proT-cell differentiation. Conversely, stiff, elastic matrices inhibit HSC commitment to the T-lineage, and rather promotes Myeloid-cell differentiation. Our observations indicate mechanical reciprocity in signaling pathways indispensable to thymopoiesis, and highlights extracellular matrix mechanics as a variable in controlling hematopoietic stem cell fate decisions.
    DOI:  https://doi.org/10.1101/2025.08.27.671384
  2. Nat Mater. 2025 Sep 05.
    Local photocrosslinking of native tissue matrix regulates lung epithelial cell mechanosensing and function.
    Donia W Ahmed, Matthew L Tan, Yuchen Liu, Jackson Gabbard, Esther Gao, Avinava Roy, Michael M Hu, Firaol S Midekssa, Miriam Stevens, Fulei Wuchu, Minal Nenwani, Jingyi Xia, Adam Abraham, Deepak Nagrath, Lin Han, Rachel L Zemans, Brendon M Baker, Claudia Loebel.
      Within most tissues, the extracellular microenvironment provides mechanical cues that guide cell fate and function. Changes in the extracellular matrix such as aberrant deposition, densification and increased crosslinking are hallmarks of late-stage fibrotic diseases that often lead to organ dysfunction. Biomaterials have been widely used to mimic the mechanical properties of the fibrotic matrix and study pathophysiologic cell function. However, the initiation of fibrosis has largely been overlooked, due to challenges in recapitulating early stages of disease progression within the native extracellular microenvironment. Here, using visible-light-mediated photochemistry, we induced local crosslinking and stiffening of extracellular matrix proteins within ex vivo mouse and human lung tissue. In ex vivo lung tissue of epithelial cell lineage-traced mice, local matrix crosslinking mimicked early fibrotic lesions that increased alveolar epithelial cell mechanosensing, differentiation, and nascent protein deposition and remodelling. However, the inhibition of cytoskeletal tension, mechanosensitive signalling pathways or integrin engagement reduced epithelial cell spreading and differentiation. Our findings emphasize the role of local extracellular matrix crosslinking and nascent protein deposition in early stage tissue fibrosis and have implications for ex vivo disease modelling and applications to other tissues.
    DOI:  https://doi.org/10.1038/s41563-025-02329-0
  3. Adv Healthc Mater. 2025 Sep 04. e02079
    Controlling Intestinal Organoid Polarity using Synthetic Dynamic Hydrogels Decorated with Laminin-Derived IKVAV Peptides.
    Laura Rijns, Joost A P M Wijnakker, Victor A Veenbrink, Riccardo Bellan, Fenna W B Craenmehr, Simone I S Hendrikse, Johnick F van Sprang, Wim de Lau, E W Meijer, Hans Clevers, Patricia Y W Dankers.
      Intestinal organoids are three-dimensional cellular structures that are cultured in laminin-rich Matrigel, yielding organoids with correct, basal-out polarity. Removal of Matrigel results in organoids with reversed, apical-out polarity, demonstrating its vital role. However, Matrigel's composition is ill-defined, and its pathogenic origin poses challenges in reproducibility. Therefore, we here introduce a fully synthetic dynamic hydrogel that presents the IKVAV peptide as a laminin-mimic for guiding intestinal organoid polarity in a minimalistic, controlled manner. The ureido-pyrimidinone moiety is used to form supramolecular hydrogels that have orthogonal control over properties, like stiffness, ligand type and concentration. It is found that the IKVAV peptide combined with integrin activating antibody TS2/16 controls intestinal organoid polarity. Increasing hydrogel dynamics (stress-relaxing half-life time of ≈1000 to 30 s) further supports the growth of intestinal organoids with correct polarity, while a bulk level of stiffness (G' ≈0.7 kPa) is crucial to offer mechanical support. Through manipulation of integrins, it is revealed that the IKVAV-organoid interaction is integrin β1-mediated. Our findings demonstrate the essential role of the IKVAV motif in guiding intestinal organoid polarity in synthetic dynamic hydrogels - paving the way for the future design of synthetic systems to culture complex living tissue.
    Keywords:  IKVAV; dynamics; intestinal organoids; laminin; polarity; supramolecular hydrogel; synthetic extracellular matrices
    DOI:  https://doi.org/10.1002/adhm.202502079
  4. Adv Healthc Mater. 2025 Sep 04. e02353
    Dynamic Macropore Formation via Dual-Degrading Injectable Microgels Enhances Host-Mediated Angiogenesis and Regeneration.
    Jiayuan Kong, Hexiang Feng, Minh Phan, Kedar Krishnan, Evan Wang, Da Peng, Collin Schmidt, Jeffrey Chen, Kailei Goodier, Zhi-Cheng Yao, Chi Zhang, Xiang Liu, Yueh-Hsun Yang, Sashank K Reddy, Hai-Quan Mao.
      Hydrogels are widely employed in tissue engineering for their biomimetic microenvironments. However, the dense crosslink network of hydrogels with matching mechanical properties of soft tissues often restricts cell infiltration and tissue integration. While granular hydrogels enhance host integration through the formation of porous channels between particles, they self-anneal in vivo, thereby limiting porosity and interconnectivity. To address this, an injectable hyaluronic acid (HA) macroporous hydrogel mixture consisting of two microgels with differential degradation profiles (faster- and slower-degrading) is designed. The faster-degrading fraction gradually generates interconnected macropores, enhancing cell infiltration throughout the mixtures, whereas the slower-degrading counterpart preserves volumetric integrity. Computational simulations refined the microgel ratio, identifying that a 1:1 volume ratio of the two microgels achieves the highest degree of host cell infiltration. The faster-degrading HA exerts biostimulatory effects in rats, recruiting and programming macrophages to a pro-regenerative phenotype and amplifying pro-angiogenic responses that are absent in macrophage-depleted rats. The dual-degrading microgels simultaneously enable gradual pore formation while maintaining structural integrity through ECM deposition by infiltrating host cells. This study presents a programmable hydrogel design that leverages dynamic macroporous structure formation to modulate host cell infiltration and tissue integration, with potential applications in soft tissue regeneration.
    Keywords:  angiogenesis; degradable biomaterials; dynamic hydrogels; macropore formation; regenerative medicine
    DOI:  https://doi.org/10.1002/adhm.202502353
  5. bioRxiv. 2025 Aug 21. pii: 2025.08.20.671360. [Epub ahead of print]
    Dynamic and atypical E-cadherin-based attachments mediate melanoblast migration through confined epithelial spaces.
    Denay J K Richards, Brandon M Trejo, Parijat Sil, Abhishek Biswas, Rebecca A Jones, Lionel Larue, Danelle Devenport.
      Epithelial tissues are populated with accessory cells such as immune cells, sensory cells, and pigment-producing melanocytes, which must migrate through and intercalate between tightly adherent epithelial cells. Although much is known about how cells migrate through interstitial spaces consisting of predominantly of collagen-rich ECM and mesenchyme, how cells migrate through confined epithelial spaces without impairing barrier function is far less understood. Here, using live imaging of the mouse epidermis, we captured the migration of embryonic melanocytes (melanoblasts) while simultaneously visualizing the basement membrane or epithelial surfaces. We show that melanoblasts migrate through both basal and suprabasal layers of the epidermis and hair follicles where they use keratinocyte surfaces, as well as the basement membrane, as substrates for migration. We show that melanoblasts form atypical and dynamic E-cadherin based attachments to surrounding keratinocytes that largely lack the cytoplasmic catenins known to anchor E-cadherin to the actin cytoskeleton. We show E-cadherin is needed in both melanoblasts and keratinocytes to stabilize migratory protrusions, and that depleting E-cadherin in melanoblasts results in reduced motility and ventral depigmentation in adult mice. These findings illustrate how migratory cells co-opt the cell-cell adhesion machinery connecting adjacent epithelial cells to invade between and migrate through them without interrupting the skin barrier.
    DOI:  https://doi.org/10.1101/2025.08.20.671360
  6. Adv Ther (Weinh). 2025 Jun 25. pii: e00067. [Epub ahead of print]
    Mechanical interactions impact the functions of immune cells and their application in immunoengineering.
    Yu-Chang Chen, Nghi M Tran, Kyle H Vining.
      Immune cells experience a wide range of modes and magnitudes of mechanical forces as they infiltrate tissues and physically interact with other cells. Biophysical forces influence cell phenotypes through mechanosensing of the cytoskeleton, cell adhesion, catch and slip bonds, and mechanically gated ion channels. As a result, different mechanical environments impact the function and expression of immune cell receptors, which subsequently affects local and systemic immune responses. Mechanical coupling of immune cell receptors can be exploited in immuno-engineering applications such as adoptive cell transfer and artificial antigen-presenting cells through biomaterial systems with tunable mechanical properties that regulate receptor expression and cell activation. This review covers immune cell receptors in the adaptive and innate immune system that respond to mechanical forces and their potential to be applied for advancing current immunotherapies.
    Keywords:  Biomaterials; Biomechanical forces; Extracellular matrix; Immune mechanobiology; Immunotherapy; Stiffness; Viscoelasticity
    DOI:  https://doi.org/10.1002/adtp.202500067
  7. Nature. 2025 Sep 03.
    Compression causes cancer cells to start spreading.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-025-02768-4
  8. Science. 2025 Sep 04. 389(6764): eadr8753
    Epithelial tension controls intestinal cell extrusion.
    Daniel Krueger, Willem Kasper Spoelstra, Dirk Jan Mastebroek, Rutger N U Kok, Shanie Wu, Mike Nikolaev, Marie Bannier-Hélaouët, Nikolche Gjorevski, Matthias Lutolf, Johan van Es, Jeroen van Zon, Sander J Tans, Hans Clevers.
      Cell extrusion is essential for homeostatic self-renewal of the intestinal epithelium. Extrusion is thought to be triggered by crowding-induced compression of cells at the intestinal villus tip. In this study, we found instead that a local "tug-of-war" competition between contractile cells regulated extrusion in the intestinal epithelium. We combined quantitative live microscopy, optogenetic induction of tissue tension, genetic perturbation of myosin II activity, and local disruption of the basal cortex in mouse intestines and intestinal organoids. These approaches revealed that a dynamic actomyosin network generates tension throughout the intestinal villi, including the villus tip region. Mechanically weak cells unable to maintain this tension underwent extrusion. Thus, epithelial barrier integrity depends on intercellular mechanics.
    DOI:  https://doi.org/10.1126/science.adr8753
  9. J Phys Chem B. 2025 Aug 28.
    Enhanced Mechanophore Activation in Hydrogel Networks Driven by Swollen Network Pretension.
    Meytal Forer, Alessio Maselli, Yifan Liao, Adan Hijaze, Thekra Msarwe, Joshua M Grolman.
      There is often a discrepancy between the strain required to activate mechanophores and incorporation in bulk materials, inhibiting these force sensors from many practical, commercial, and biological uses. The difference is particularly pronounced for biomimetic networks such as viscoelastic hydrogels, in which the distribution of strain is unclear due to dissipation. Here, we show that the activation of spiropyran mechanophores in alginate networks is related to cross-linking characteristics by comparing ionic and covalent bonds. Through a simple shear force setup using syringes and Bernoulli's principle, we observe higher activation of spiropyran in ionic gels, regardless of mechanical versus ultraviolet light stimulus. This may be predominantly driven by differences in network pretension due to swelling, as the ring-closing reaction of merocyanine to spiropyran was similarly affected. These insights shed new light on understanding force propagation in complex networks, leading to higher mechanophore sensitivities in biologically similar materials.
    DOI:  https://doi.org/10.1021/acs.jpcb.5c02492
  10. Biol Open. 2025 Sep 01. pii: bio.062021. [Epub ahead of print]
    Physical confinement and phagocytic uptake induce persistent cell migration.
    Summer G Paulson, Sophia Liu, Jeremy D Rotty.
      Physical confinement is not routinely considered as a factor that influences phagocytosis, which is typically investigated using unconfined in vitro assays. BV2 microglia-like cells were used to interrogate the impact of confinement on IgG-mediated phagocytosis side by side with unconfined cells. Confinement acted as a potent phagocytic driver, greatly increasing the fraction of phagocytic cells in the population compared to the unconfined setting. Arp2/3 complex and myosin II contributed to this effect. Remarkably, confinement partially rescued phagocytic uptake upon myosin II disruption. In addition, cells under confinement were partially resistant to the actin-depolymerizing drug cytochalasin D. Unexpectedly, we observed that bead uptake stimulated persistent migration, a process we term 'phagocytic priming'. Integrin-dependent adhesion was required for phagocytic priming in unconfined and confined settings, but was dispensable for phagocytic uptake. The cytoskeletal requirements for phagocytic priming differed depending on confinement state. Myosin II and Arp2/3 complex were required for phagocytic priming under confinement, but not in unconfined settings. As with phagocytosis, cytoskeleton-dependent priming of motility varies based on physical confinement status. Phagocytic priming may be a crucial innate immune mechanism by which cells respond to wounds or trauma with increased surveillance of the local microenvironment.
    Keywords:  Actin; Arp2/3 complex; Confined motility; Fibronectin; Microglia; Myosin; Phagocytosis
    DOI:  https://doi.org/10.1242/bio.062021
  11. ACS Appl Mater Interfaces. 2025 Aug 28.
    Curved Magnetic Hydrogels for Understanding Cancer Initiation.
    Ana C Manjua, Christian M Verkerk, Burcu Gumuscu.
      Cancer development is increasingly associated with changes in tissue curvature, which influence dynamic cellular behaviors such as polarization and migration. However, the mechanisms by which curved tissue architectures contribute to cancer progression remain poorly understood, partly due to the lack of adequate research tools. Here, we fabricated magnetic Acrylamide hydrogel constructs to investigate the effect of curvature and dynamic movement induced by external magnetic fields of low intensity (100 mT) in the phenotype and gene expression of MDA-MB-231 metastatic breast cancer cells. We found that combining the magnetic hydrogel (MACrylamide) with an applied magnetic field significantly reduced the area occupied by the cells, from 55% to 33%, compared to conditions without magnetic field exposure. In addition, exposure to the magnetic field in combination with the magnetic scaffold had a statistically significant effect on the expression of specific genes associated with anti-inflammatory responses and tumor proliferation and metastasis (NMO1, OCT4, SOX4). These findings suggest that the cells altered their behavior after 7 days of culture on the magnetic hydrogel and 24 h of magnetic stimulation. As a control, NHDF dermal fibroblasts were cultured under the same conditions. Comparison of the two cell lines confirms the selectivity of the approach for cancer cells while ensuring minimal impact on healthy skin cells. This work underscores the importance of dynamic tissue curving during carcinogenesis using a biocompatible surface that mimics physiologically relevant curved tissues.
    Keywords:  MDA-MB-231 breast cancer cells; NHDF dermal fibroblasts; cancer cell dynamics; curved scaffold; magnetic nanoparticles; magnetic scaffold; polyacrylamide
    DOI:  https://doi.org/10.1021/acsami.5c11408
  12. Small. 2025 Aug 28. e03351
    Bioassembly of Myoblast Spheroids in Electrofibrillated Scaffolds for 3D Muscle Tissue Biofabrication.
    Corinna Heinze, Camilla Mussoni, Matthias Ryma, Csaba Gergely, Zan Lamberger, Anna Schäfer, Kristina Andelovic, Philipp Stahlhut, Gregor Lang, Jürgen Groll, Taufiq Ahmad.
      One of the key challenges in tissue engineering is recreating the extracellular matrix (ECM), which is essential for cell function, especially in anisotropic tissues like muscle, where tissue morphology dictates contraction and motion. The recently developed method of melt electrofibrillation offers a promising platform for producing highly aligned nanofibrillar scaffolds that mimic collagen. These scaffolds are created by melt electrowriting a blend of polycaprolactone (PCL) and polyvinyl acetate (PVAc), which are precisely printed in a box geometry. After washing out the PVAc, aligned nano-scaled PCL fibrils remain. These fibers provide extracellular matrix-like cues for cells to mature, encouraging them to align and interact with the structure. This study showcases the application of C2C12 muscle cells, which are assembled into spheroids and seeded on the scaffolds. Over 21 days, the cells align along the fibrils, colonize the scaffold, and, when exposed to differentiation media, begin forming early-stage myotubes and express myogenic factors, such as Myogenin. This demonstrates that the synthetic matrix is a useful tool for studying the interaction of aligned 3D matrices in muscle tissue differentiation.
    Keywords:  extracellular matrix; melt electrofibrillation (MEF); melt electrowriting (MEW); muscle tissue engineering; spheroids
    DOI:  https://doi.org/10.1002/smll.202503351
  13. Sci Adv. 2025 Aug 29. 11(35): eadw6446
    3D printed anisotropic tissue simulants with embedded fluid capsules for medical simulation and training.
    Adarsh Somayaji, Matthew S Lawler, Alex T Gong, Zachary J Fuenning, Victoria A Roach, Athira B S, David J Traina, Jason R Speich, Ruikang K Wang, Matthew G Hackett, David M Hananel, Robert M Sweet, Michael C McAlpine.
      Human tissues are primarily composed of collagen and elastin fiber networks that exhibit directional mechanical properties that are not replicable by conventional tissue simulants manufactured via casting. Here, we 3D print tissue simulants that incorporate anisotropic mechanical properties through the manipulation of infill voxel shape and dimensions. A mathematical model for predicting the anisotropy of single- and multimaterial structures with orthogonal infill patterns is developed. We apply this methodology to generate conformal printing toolpaths for replicating the structure and directional mechanics observed in native tissue within 3D printed tissue simulants. Further, a method to embed fluid-filled capsules within the infill structure of these tissue simulants to mimic blood is also presented. The improvements in simulation quality when using 3D printed anisotropic tissue simulants over conventional tissue simulants are demonstrated via a comparative acceptability study. These advances open avenues for the manufacture of next-generation tissue simulants with high mechanical fidelity for enhanced medical simulation and training.
    DOI:  https://doi.org/10.1126/sciadv.adw6446
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