bims-ecemfi Biomed News
on ECM and fibroblasts
Issue of 2026–08–02
twelve papers selected by
Badri Narayanan Narasimhan, University of California, San Diego
  1. Photoresponsive Granular Hydrogels Enable Spatiotemporal Control of Matrix Mechanics and MSC Behavior.
  2. Microscale matrix defects suppress tension-dependent protrusions and stall collective cell migration.
  3. Photosoftening Macroporous Hydrogels for Dynamic Tissue Engineering.
  4. Protocol for optogenetic stimulation of cells under physical confinement.
  5. Development and Characterization of a FRET-based Formin Tension Sensor in Living Cells.
  6. Non-Contact Transspatial Regulatory Function of the Extracellular Matrix.
  7. Basement membrane turnover controls cell shape.
  8. A geometric-surface PDE model for cell-nucleus translocation through confinement.
  9. Kalman-filter force inference: an estimation framework for cellular forces from temporal evolution of epithelial morphogenesis.
  10. A Mathematical Model for Chemo-Mechanically Induced Collective Cell Motility on Planar Elastic Substrates.
  11. Associating the morphology of helper T cells with cytokine activity through imaging flow cytometry and deep learning.
  12. Extracellular Matrix Proteomic Signatures Associate with Disease-Free Survival in Later Events of Ductal Carcinoma In Situ or Invasive Breast Cancer.
  1. Adv Mater. 2026 Jul 28. e74258
    Photoresponsive Granular Hydrogels Enable Spatiotemporal Control of Matrix Mechanics and MSC Behavior.
    Nicole E Friend, Nolan R Petrich, Kara E Shockley, Ashbey N Manning, Matthew W Jaeschke, Daniel Saeb, Mark W Young, Kristi S Anseth.
      Granular hydrogels offer a powerful platform for engineering porous, cell-instructive scaffolds with tunable mechanical, structural, and biochemical properties, yet introducing spatial and functional heterogeneity typically requires multiple microgel populations or complex fabrication strategies. Here, we present a programmable, photoresponsive granular hydrogel platform that enables post-assembly spatiotemporal control of scaffold mechanics and cell microenvironments from a single microgel formulation. Poly(ethylene glycol) microgels containing photolabile allyl sulfide moieties were synthesized via strain-promoted azide-alkyne cycloaddition and assembled into granular scaffolds capable of light-mediated remodeling through radical addition-fragmentation chain transfer. This chemistry afforded dynamic, on-demand, and spatially defined tuning of mechanical properties (G' = 0.7-3.7 kPa) while maintaining scaffold porosity (∼20%). High-resolution photopatterning across multiple length (6 µm-1 mm) and timescales enabled precise modulation of local microenvironments. Human mesenchymal stem/stromal cells embedded in these scaffolds responded to spatiotemporal modulation of matrix mechanics as observed by changes in morphology, yes-associated protein 1 (YAP) nuclear localization, and secretory profiles. Together, these results establish a versatile and broadly applicable strategy for programming mechanical heterogeneity and regulating cell behavior in granular hydrogels through photolabile moieties.
    Keywords:  granular hydrogels; mechanosensing; mesenchymal stem/stromal cells; microgels; photodegradation; photopatterning; stiffness
    DOI:  https://doi.org/10.1002/adma.74258
  2. Cell Rep. 2026 Jul 31. pii: S2211-1247(26)00832-6. [Epub ahead of print] 117754
    Microscale matrix defects suppress tension-dependent protrusions and stall collective cell migration.
    Hannah Zmuda, Diego Barra Avila, Ping-Hsien Lee, Christopher Walter, Amit Pathak.
      During development, wound repair, and disease, epithelia must detect and respond to subtle extracellular defects to maintain coordinated migration. We show that collectively migrating epithelia undergo large-scale spatiotemporal stalling in response to laser-ablated micro-defects in the presence of collagen type IV. When the filopodia of leading-edge cells encounter micro-defects, the resulting local cytoskeletal disruption propagates to the follower cells, producing multicellular stalling over length scales much larger than the original defect. Extracellular changes in matrix stiffness, collagen type, and osmolarity regulate cell stiffness and membrane tension, which, in turn, control protrusive activity and stall migration. Through these extracellular variations, we found that stiffer cells and lower membrane tension suppress protrusions in leader cells, which enhances multicellular stalling through intercellular propagation of cytoskeletal disruption. This work advances the biophysical understanding of cell migration by showing that collagen-IV, softer matrices, and hypertonic media enhance cellular sensing of extracellular defects and wounds.
    Keywords:  CP: Cell biology; basement membrane; cell stiffness; collagen; collective cell migration; extracellular matrix; mechanobiology; membrane tension
    DOI:  https://doi.org/10.1016/j.celrep.2026.117754
  3. bioRxiv. 2026 Jul 14. pii: 2026.07.13.737088. [Epub ahead of print]
    Photosoftening Macroporous Hydrogels for Dynamic Tissue Engineering.
    Golnaz Navidi, Ben Canter, Ella Morris, Teresa L Rapp.
      With the push towards accessible benchtop models to capture biological events, many researchers are reaching for hydrogel platforms for 3D tissue engineering ex vivo. Recapitulating the dynamic mechanical environment cells experience in vivo requires dynamic hydrogel scaffolds whose mechanical properties can be reprogrammed with spatiotemporal precision. Here we describe a chemically simple hydrogel platform that undergoes visible-light photosoftening via a ruthenium-based photocleavable crosslinker, leveraging tetrazine-norbornene inverse electron demand Diels Alder (iEDDA) click chemistry between RuTetrazine crosslinker and norbornene-modified hyaluronic acid (NorHA). Nitrogen gas evolved during this reaction is repurposed as an intrinsic porogen, nucleating macropores (55-175 µm) directly during gelation. Initial stiffness (1.5-10 kPa) and softening extent (from 50%-100% drop in storage modulus) are independently tunable through polymer and crosslinker composition. We have found RuTetrazine to be non-mutagenic and non-toxic (>80% live cell populations) once network-bound (IC50 = 0.27 mM). In a cell-instructive network co-crosslinked with an MMP-RGD-bearing peptide, human mesenchymal stromal cells (hMSCs) photosoftened in situ (2.27→0.54 kPa, ∼76%) spread approximately six-fold relative to stiff controls (∼6,500 vs. ∼1,100 µm 2 , p < 0.0001). This work demonstrates a synthetically accessible photocleavable crosslinker and a simple, macroporous hydrogel for modulating dynamic mechanical cues in three dimensions.
    DOI:  https://doi.org/10.64898/2026.07.13.737088
  4. STAR Protoc. 2026 Jul 30. pii: S2666-1667(26)00407-7. [Epub ahead of print]7(3): 104754
    Protocol for optogenetic stimulation of cells under physical confinement.
    Qinling Yuan, Alice Amitrano, Debanik Choudhury, Konstantinos Konstantopoulos.
      Optogenetic approaches enable spatiotemporal control of signaling proteins, yet their integration with microfluidic assays to study confined cell migration remains challenging. Herein, we present a protocol for the optogenetic activation of PI3K/Akt signaling in confined cells. We detail procedures for applying stimulation to induce localized Akt activation at the cell's leading edge. This protocol enables real-time manipulation of subcellular signaling dynamics during confined migration. For additional information on the use of this protocol, please refer to Lee et al.1.
    Keywords:  Biophysics; Biotechnology and bioengineering; Cancer; Cell Biology
    DOI:  https://doi.org/10.1016/j.xpro.2026.104754
  5. bioRxiv. 2026 Jul 13. pii: 2026.07.11.737992. [Epub ahead of print]
    Development and Characterization of a FRET-based Formin Tension Sensor in Living Cells.
    Philip Bleicher, John A Hammer, James R Sellers, Anjelika Gasilina.
      Mechanotransduction via the actin cytoskeleton is linked to fundamental cellular processes such as morphogenesis, cell division, and motility, requiring the control of tensile forces mediated by the motor protein non-muscle myosin 2 (NM2). Formins such as mDia1 have been shown to elongate actin structures that are under mechanical tension; conversely, mDia1's elongation rates are modulated by the applied force. Despite their relevance at the membrane/cortex interface, reported values for tension in formin-elongated actin filaments stem from theoretical estimates and simulations, but have not been amenable experimentally so far. Thus, we developed a Förster resonance energy transfer (FRET)-based, tension-sensitive probe (mDia1TS) and quantified the measured tension in live U2OS cells using fluorescence lifetime imaging microscopy (FLIM). Through whole-cell ROI analysis we show a short and long lifetime component, reporting an intensity-weighted, averaged lifetime corresponding to ∼3.5 pN. Upon mitogen stimulation of cells using EGF, we show that the tension homeostasis changed significantly, with a measurable increase in tension in the cell's periphery and relaxation in its center. Furthermore, the reported average tension relaxed by 2 pN after adding the NM2 inhibitor para-nitroblebbistatin. We utilized siRNA knockdowns of individual NM2 paralogs (NM2-A, NM2-B, or NM2-C) to measure their individual contribution, revealing NM2-A as the main paralog to produce tensile force in this system. Taken together, we demonstrate that mDia1TS is able to directly determine that active mDia1 in cells is under tension, and that subcellular quantification with pN precision is possible.
    Significance: Despite the fundamental importance of formins in regulating actin-based processes, reported values for tension in formin-mediated actin structures stem from simulations and theoretical estimates. In this study we developed a FRET-based, tension-sensitive reporter probe for formin mDia1, which we termed mDia1TS. Given the expanding clinical spectrum of DIAPH1/mDia1 mutations, our tool mDia1TS provides a quantitative tool for elucidation of changes in cytoskeletal assemblies.
    DOI:  https://doi.org/10.64898/2026.07.11.737992
  6. Smart Med. 2026 Aug;5(4): e70046
    Non-Contact Transspatial Regulatory Function of the Extracellular Matrix.
    Ting Cao, Chen Yang, Zhengyang Wang, Changmin Shao, Ziye Xu, Baode Chen, Jiayu Zhang, Yongcheng Wang, Fangfu Ye.
      As a crucial biological material, the extracellular matrix (ECM) constitutes a major part of the extracellular microenvironment, offering both structural support and essential biological signals to surrounding cells. Research into ECM properties not only deepens our understanding of cellular behavior and metabolism but also opens new avenues for studying disease mechanisms and therapies. In this work, we report a previously unrecognized function of ECM by leveraging a three-dimensional spatial cavity structure. It is termed "Non-contact Transspatial Regulatory" (nCTR), referring to the ECM that remotely regulates cells without traditional direct physical contact. Systematic investigation and validation of key factors reveal that nCTR strongly depends on the 3D spatial distance between ECM and cells, governed by both physical spatial confinement and chemical signaling exchange. The process involves multiple components, pathways, and mechanisms, with macropinocytosis playing a dominant role. This newly identified function of the ECM offers a fresh perspective on cellular behavior and will undoubtedly open a new frontier in the cellular microenvironment studies.
    Keywords:  extracellular matrix; macropinocytosis; non‐contact; remote regulatory
    DOI:  https://doi.org/10.1002/smmd.70046
  7. Cell. 2026 Jul 30. pii: S0092-8674(26)00808-1. [Epub ahead of print]
    Basement membrane turnover controls cell shape.
    Ricardo Barrientos, Billie Meadowcroft, Besaiz J Sánchez-Sánchez, Brian M Stramer, Ewa K Paluch, Guillaume Charras, Shiladitya Banerjee, Anđela Šarić, Yanlan Mao.
      The regulation of 3D cell shape is a fundamental problem of life. In multicellular tissues, cell shape emerges through the balance of forces inside and outside the cell. In epithelia, the basement membrane (BM) is the first extracellular barrier that cells sense biochemically and mechanically. Despite this, little is known about how BM mechanical properties are regulated and how they impact cell shape. Through mathematical modeling, we show that the stress relaxation time of the BM can regulate cell shape. Using molecular dynamics simulations, we show that the stress relaxation time of a collagen IV network can be inferred from the lifetime of collagen IV molecules. To measure collagen IV lifetime in vivo, we develop a fluorescent timer reporter for collagen IV and show that perlecan modifies collagen IV lifetime. This cross-disciplinary approach establishes a multiscale framework to probe matrix turnover, and its regulation and function in cell shape control.
    Keywords:  basement membrane; cell shape; extracellular matrix remodeling; mechanobiology; morphogenesis; physical modeling; protein turnover
    DOI:  https://doi.org/10.1016/j.cell.2026.07.010
  8. PLoS Comput Biol. 2026 Jul 30. 22(7): e1014569
    A geometric-surface PDE model for cell-nucleus translocation through confinement.
    Francesca Ballatore, Anotida Madzvamuse, Cécile Jebane, Emmanuèle Helfer, Rachele Allena.
      Understanding how cells migrate through confined environments is crucial for elucidating fundamental biological processes, including cancer invasion, immune surveillance, and tissue morphogenesis. The nucleus, as the largest and stiffest cellular organelle, often limits cellular deformability, making it a key factor in migration through narrow pores or highly constrained spaces. In this work, we introduce a geometric surface partial differential equation (GS-PDE) model in which the cell plasma membrane and nuclear envelope are described as evolving energetic closed surfaces governed by force-balance equations. We replicate the results of a biophysical experiment, in which a microfluidic device is used to impose compressive stresses on cells by driving them through narrow microchannels under a controlled pressure gradient. The model is validated by reproducing cell entry into the microchannels. A parametric sensitivity analysis highlights the dominant influence of specific parameters, whose accurate estimation is essential to faithfully capture the experimental setup. We found that surface tension and confinement geometry emerge as key determinants of translocation efficiency. Although tailored to this specific setup for validation purposes, the framework is sufficiently general to be applied to a broad range of cell mechanics scenarios, providing a robust and flexible tool for investigating the interplay between cell mechanics and confinement. It also offers a solid foundation for future extensions integrating more complex biochemical processes such as active confined migration.
    DOI:  https://doi.org/10.1371/journal.pcbi.1014569
  9. J R Soc Interface. 2026 Jul 29. pii: 20260017. [Epub ahead of print]23(240):
    Kalman-filter force inference: an estimation framework for cellular forces from temporal evolution of epithelial morphogenesis.
    Goshi Ogita, Takemasa Miyoshi, Tatsuo Shibata.
      Epithelial morphogenesis is orchestrated by cellular forces, including cell junctional tension and cellular pressure. Elucidating their spatio-temporal dynamics is paramount for understanding morphogenesis during development. While various methods have been proposed to infer cellular forces from the shape and geometry of cells within epithelial tissues, most rely on the assumption of static force balance, which neglects cell deformation, thereby limiting their applicability to tissues undergoing dynamic deformation. To address this, we develop a novel method to accurately infer cellular forces from time-lapse imaging data by explicitly accounting for tissue dynamics. Our method rests on two fundamental assumptions. First, cellular forces balance dissipative forces (viscous and frictional forces) arising from cell deformation, termed the dynamic force balance. Second, cellular forces evolve smoothly. A Bayesian formalization of these assumptions yields a new force inference approach: Kalman-filter force inference. We evaluated our method using synthetic data from cell vertex model simulations. The results demonstrated accurate estimation of cellular force dynamics across diverse cell mechanical parameters. Furthermore, the method proved robust to observation noise. Our method will broaden the applicability of force inference and provide new insights into the mechanical principles underlying epithelial morphogenesis.
    Keywords:  epithelial morphogenesis; force/stress inference; statistical inference; tissue mechanics
    DOI:  https://doi.org/10.1098/rsif.2026.0017
  10. Int J Numer Method Biomed Eng. 2026 Aug;42(8): e70201
    A Mathematical Model for Chemo-Mechanically Induced Collective Cell Motility on Planar Elastic Substrates.
    Riham K Ahmed, Tamer Abdalrahman, Neil H Davies, Fred Vermolen, Thomas Franz.
      Cells interact with mechanical and chemical environmental cues, such as mechanical cues from other cells and chemical signals from growth factors. The current study aims to develop a mathematical model for combined chemically and mechanically induced collective cell motility on planar substrates. The mechanically induced cell motility is simulated using strain energy density gradients generated in an elastic substrate by cellular traction forces. For chemotaxis, Green's function and Duhamel's principle are used to solve the diffusion equation that describes the distribution of a growth factor and to represent chemo-mechanically induced deterministic collective cell motility on planar elastic substrates. Chemically induced motility of cells towards a growth factor source is predicted for different growth factor production and diffusion rates. Chemo-mechanical cues with varying growth factor production and diffusion rates are explored for the motility of four cells and one motile cell in the presence of one stationary cell. The developed model describes the chemo-mechanically induced motility of individual cells on planar substrates. The model provides valuable information for in vivo or in vitro studies due to its suitability for extension to other chemical source shapes, mobilised sources, many sources, and soluble concentration gradients.
    Keywords:  cell motility; diffusion rate; growth factor; production rate; strain energy density
    DOI:  https://doi.org/10.1002/cnm.70201
  11. Lab Chip. 2026 Jul 31.
    Associating the morphology of helper T cells with cytokine activity through imaging flow cytometry and deep learning.
    Natsumi Tiffany Ishii, Ikuo Hieda, Yaqi Zhao, Tatsuhiko Akiyama, Yingdong Luo, Kazuma Kita, Yuma Oka, Masatoshi Yanagida, Tianben Ding, Keisuke Goda.
      The immune system protects the body from foreign substances, such as viruses and bacteria. Among its key orchestrators are helper T cells, which coordinate immune responses by activating other immune cells to eliminate these threats. Helper T cell activation has been widely studied, often by stimulating cells in vitro and measuring changes in receptor expression. However, systematic assessment of activation at scale remains challenging because it requires both large single-cell imaging datasets and advanced computational methods to analyse complex morphological features. Here, using imaging flow cytometry and deep learning, we show that morphological information is crucial for identifying high-activity T cells. We also demonstrate that receptor clustering may associate with high cytokine activity. These findings provide a new perspective for assessing treatment options for patients with immune-related diseases.
    DOI:  https://doi.org/10.1039/d6lc00113k
  12. bioRxiv. 2026 Jul 21. pii: 2026.07.16.738889. [Epub ahead of print]
    Extracellular Matrix Proteomic Signatures Associate with Disease-Free Survival in Later Events of Ductal Carcinoma In Situ or Invasive Breast Cancer.
    Taylor S Hulahan, Laura Spruill, Bryn Gerding, Jade K Macdonald, Harrison B Taylor, Mengjun Wang, Elizabeth Wallace, Siri H Strand, Anand S Mehta, Marvella E Ford, Harikrishna Nakshatri, Jeffrey R Marks, Robert M Angelo, Graham A Colditz, E Shelley Hwang, Richard R Drake, Robert West, Peggi M Angel.
       Background: Ductal carcinoma in situ (DCIS) is a noninvasive breast lesion with variable risk of progression to invasive breast cancer (IBC). Current transcription and cell marker investigations suggest ECM decreases in later events but are limited in details of ECM proteomic composition, including post-translational modifications. We investigated whether the extracellular matrix (ECM) proteome alters with later breast events of DCIS or IBC.
    Methods: ECM-targeted mass spectrometry imaging and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were applied to ten tissue microarrays from the Resource of Archival Human Breast Tissue cohort (RAHBT). Primary DCIS specimens (n=136) were analyzed in relation to later events of DCIS (n=40) or IBC(n=30), with a mean follow-up of 192.1 months 95% CI [179.1,205.1]. Statistical modeling, survival analyses, and exploratory machine learning approaches were used to identify ECM peptide signatures associated with later events.
    Results: Distinct ECM peptide profiles were associated with later events of DCIS or IBC. Fifteen peptides derived from fibrillar collagens (COL1A1, COL1A2, COL3A1) and elastin, showed significantly reduced abundance in patients who developed IBC. Lower expression of specific collagen peptides associated with overall 19.9% 95% CI [17.92, 21.81] decreased disease-free survival for IBC. Lower expression of these peptides was significantly associated with reduced disease-free survival (age-adjusted hazard ratio [HR] = 2.45, 95% CI: 2.33-2.57; P < 0.05). Patient-matched samples of primary DCIS, later DCIS, and later invasive breast cancer further demonstrated reduction in ECM peptide detection. Exploratory predictive modeling from patient-matched samples achieved high performance (AUROC >0.98, accuracy >93%) in distinguishing primary from later events. Following prior work in the RAHBT cohort, reduction of certain collagen peptides was also observed in primary DCIS samples from higher risk patient groups.
    Conclusions: ECM proteomic remodeling, particularly decreases of specific collagen domains, is strongly associated with later events of DCIS and IBC. These findings highlight ECM proteome as a critical regulator of breast cancer emergence with potential as a prognosticator of risk stratification to guide clinical management of DCIS.
    DOI:  https://doi.org/10.64898/2026.07.16.738889
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