bims-ecemfi 2026-09-13 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2026–09–13
twelve papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Confinement controls the stochastic onset of single-cell rotation.
Controlling viscoelastic behavior and microstructural organization in engineered living materials using synthetic adhesins and rheometry.
Fibrotic Substrate Stiffness Enhances Endometriotic Epithelial Cell Motility.
Decoding spatiotemporal fibrotic and cellular immunosuppression of therapeutic T cells in live pancreatic ductal adenocarcinoma.
Multicellular rosette formation guides epithelial tissue assembly in pancreatic ductal adenocarcinoma cell organoids.
Clusters, fingers, and singles: A mechanical landscape of tumor invasion.
Extracellular matrix composition and stiffness regulates progesterone responsiveness and decidualization.
Cell-body curvature reduces stall frequency to enhance Vibrio cholerae swimming and chemotaxis through hydrogels.
Spatiotemporal modeling of focal adhesion growth on viscoelastic substrate.
A pancreatic cancer organoid-macrophage co-culture using starPEG-heparin hydrogel deciphers tumor-immune cell interactions.
Centrosome migration and apical membrane formation during epithelial polarization in MDCK cysts.
Synergistic Tuning of Pore Architecture and Mechanical Properties in a Biomimetic COL-HA-PVA Hydrogel Directs BMSC Chondrogenesis for Osteochondral Regeneration.

Proc Natl Acad Sci U S A. 2026 Sep 15. 123(37): e2602259123

Confinement controls the stochastic onset of single-cell rotation.

Sebastián Echeverría-Alar, Badri Narayanan Narasimhan, Stephanie I Fraley, Wouter-Jan Rappel.

  Single cells confined by the extracellular matrix can exhibit rotational motion, yet the physical mechanisms underlying its onset and persistence remain unclear. Here, we address this gap with a cellular phase field model that couples cell deformation, cell polarization governed by stochastic excitable dynamics, and confinement. We identify the confinement strength as a bifurcation parameter determining three regimes: Strong confinement prevents rotation through spatial constraints, intermediate confinement induces stochastic transitions between rotating and nonrotating states, and weak confinement allows persistent rotations. For the intermediate regime, we develop a semi-Markovian renewal process framework that characterizes the stochastic dynamics through dwell time statistics, transition probabilities, and first-passage times. For the weak confinement regime, we reveal that a mechanochemical feedback enables coherent rotations despite internal noise through the reduction of local excitability mediated by mechanical contraction. We formalize this feedback analytically using Kramers escape theory. Experiments on epithelial MCF10A cells in Matrigel demonstrate three types of cell dynamics that recapitulate those observed in each confinement regime. Our results establish a theoretical approach for understanding single-cell rotations under confinement, with implications for controlling single-cell dynamics by tuning extracellular matrix properties.

Keywords:  ECM confinement; actin waves; epithelial cells; mechanochemical feedback; stochastic excitable systems

DOI:  https://doi.org/10.1073/pnas.2602259123
Acta Biomater. 2026 Sep 08. pii: S1742-7061(26)00576-3. [Epub ahead of print]

Controlling viscoelastic behavior and microstructural organization in engineered living materials using synthetic adhesins and rheometry.

Stefana A Costan, Kira M Hallerbach, Samuel Y Kim, Chris Camp, Minkyu Kim, Ingmar H Riedel-Kruse.

  Engineered living materials (ELMs) at the multicelluar level represent an innovation that promises programmable properties for various applications. However, the rational tuning of the mechanical properties of such ELMs from first principles remains a challenge. Here we use synthetic cell-cell adhesins to systematically characterize how rheological and viscoelastic properties of multicellular materials made from living bacteria can be tuned through adhesion strength, cell size, cell shape, and adhesion logic. We find that many of the previous results obtained for non-living materials also apply to bacterial ELMs. Additionally, the incorporation of synthetic adhesins, combined with the adaptability of bacterial cells in modifying various cellular parameters, constitutes a new approach for the precise control over material properties. Furthermore, we demonstrate that rheology is a powerful tool for actively shaping the microscopic structure of ELMs, enabling control over cell aggregation and particle rearrangement, a key feature for complex material design. These results deepen our understanding of tuning the viscoelastic properties and fine structure of ELMs for bioprinting, microbial consortia design, and biomedical applications. Statement of significance The fields of Engineered Living Materials (ELMs) and Synthetic biology undergo rapid synergistic advancements, with bacterial and eukaryotic cells serving as modular building blocks for programmable materials. A critical challenge lies in the precise control and tunability over the mechanical and structural properties of ELMs. This paper demonstrates (1) the tunability of material viscoelasticity through key cellular parameters, i.e., adhesin strength, adhesion logic, cell shape, and multi-component mixing ratios; and (2) the generation of spatially defined colloidal consortia, mesoscopic structuring, pore formation and defect minimization through rheological manipulations. This paper bridges gaps between synthetic biology and materials science by providing a quantitative basis for ELM design and characterization, and by extending results from non-living particle suspensions to ELMs.

Keywords:  Bacteria; Engineered living materials; Rheology; Structure formation; Synthetic adhesins; Synthetic biology; Viscoelasticity

DOI:  https://doi.org/10.1016/j.actbio.2026.08.044
Tissue Eng Part A. 2026 Sep 10. 19373341261486719

Fibrotic Substrate Stiffness Enhances Endometriotic Epithelial Cell Motility.

Shohini Banerjee, Nane Manukyan, Kimberly M Stroka.

  Fibrosis is a common pathological feature of inflammatory conditions across various organ systems, leading to a marked increase in matrix stiffness. The effects of substrate stiffness on benign epithelial cells in fibrotic microenvironments remain less well characterized compared with malignant cell types. We used an endometriotic epithelial cell line and polyacrylamide hydrogels with tunable stiffness to model mechanically driven single-cell and multicellular migration. We identified a biphasic relationship between substrate stiffness and epithelial migration, where substrates of intermediate stiffness best promoted cell speed, actin stress fiber formation, focal adhesion presentation, and spheroid expansion compared with the soft and very stiff gel substrates. Increasing cellular contractility on the soft substrate and decreasing contractility on the fibrotic stiffness substrate led to an increase and decrease in cell speed, respectively. These findings suggest a role for how fibrosis as a biomechanical state regulates epithelial cell migration during the pathogenesis of benign yet invasive conditions.

Keywords:  cell migration; contractility; endometriosis; fibrosis; in vitro model; mechanobiology; substrate stiffness

DOI:  https://doi.org/10.1177/19373341261486719
Mol Syst Biol. 2026 Sep 10.

Decoding spatiotemporal fibrotic and cellular immunosuppression of therapeutic T cells in live pancreatic ductal adenocarcinoma.

Guhan Qian, Hongrong Zhang, Ingunn M Stromnes, Kevin W Eliceiri, Paolo P Provenzano.

Pancreatic ductal adenocarcinoma (PDA) is profoundly immunosuppressive. To help define this behavior, we present integrated experimental and computational frameworks to elucidate therapeutic T cell dynamics. Through the development of TME-CARTographer (TME-CART), a computational pipeline integrating high-dimensional data, graph theory, behavior analysis, and deep learning (DL), we present quantitative insights on 4D T cell-TME interactions in live PDA tumors. Mapping physical immunosuppression demonstrates that collagen fiber architectures direct migration while concomitantly limiting off-axis movement, creating immune exclusion zones. Expanding these findings, we establish that the collagen matrix harbors and spatially organizes immunosuppressive myeloid cells to serve as cooperative co-modulators of T cell behaviors, including migration, sampling, repulsion, and sequestration. Consistent with these findings, DL defines both linear and nonlinear collagen matrix and cellular neighborhood interactions as drivers of T cell behavior. The TME-CART DL framework also accurately predicts shifts in immunosuppression following depletion of myeloid cells. Overall, we identify synergistic barriers impeding anti-tumor T cell behaviors and present TME-CART as a discovery platform for interpreting complex 4D data to enhance the understanding and design of immunotherapies.

DOI: https://doi.org/10.1038/s44320-026-00243-4
Proc Natl Acad Sci U S A. 2026 Sep 15. 123(37): e2512284123

Multicellular rosette formation guides epithelial tissue assembly in pancreatic ductal adenocarcinoma cell organoids.

Marion K Raich, Fridtjof Brauns, Tamara Müller, Maximilian Reichert, Andreas R Bausch.

  Mesenchymal-to-epithelial transitions are essential for epithelial tissue formation and thus the development of functional organs. Here, we demonstrate that the transition from a disordered mesenchymal state to a columnar epithelial structure in branched pancreatic ductal adenocarcinoma organoids is associated with rosette formation. We show that fluctuations in acto-myosin contractions on the emerging apical side of branches with high cell density create a tug-of-war mechanism, leading to regular spacing of rosettes. The distance between adjacent rosettes depends on the branch diameter, which we validate with a minimal theoretical model based on apical constriction. The resulting lumen formation occurs through the apoptosis of an inner cell mass, leaving an epithelial layer lining the cavity. In summary, our findings show that rosette architecture is set by geometrical confinement of the cell nuclei in combination with acto-myosin driven contractions. This underscores the critical role of mechanical processes in self-organized assembly of epithelial tissue.

Keywords:  PDAC organoids; acto-myosin fluctuations; mesenchymal-to-epithelial transition; nuclear packing; rosette formation

DOI:  https://doi.org/10.1073/pnas.2512284123
PLoS Comput Biol. 2026 Sep;22(9): e1014747

Clusters, fingers, and singles: A mechanical landscape of tumor invasion.

Sheriff Akeeb, Adam I Marcus, Yi Jiang.

Collective invasion is a key mechanism by which tumors disseminate and metastasize, involving coordinated migration of heterogeneous cell populations. Experimental studies in spheroid-based assays have identified specialized leader and follower cells that work together during this process, but the biophysical rules governing their interaction remain unclear. We present a mechanistic, cell-based computational model using the Cellular Potts framework to investigate how heterotypic adhesion, leader motility, and follower proliferation jointly shape invasion. Leader-follower tumors were simulated across 13 310 parameter sets, and invasion was quantified by invasive and infiltrative areas, finger-like protrusions, solitary defectors, and detached clusters. From these simulations, we identified four distinct invasion phenotypes: non-invasive, bulk collective, single-cell, and multimodal. Multimodal invasion-the coexistence of cohesive strands, solitary cells, and small clusters-emerged as the most prevalent phenotype, particularly under moderate adhesion and high motility. Proliferation increased tumor bulk rather than determining invasion mode, which was governed primarily by adhesion and leader motility. Mapping outcomes across the parameter space revealed sharp transitions between invasion modes, underscoring trade-offs between adhesion and motility in shaping invasion complexity. Our results show that hybrid invasion behaviors, previously considered rare, arise robustly from simple mechanical rules and are favored in a broad region of the parameter space. This framework reconciles binary models of invasion with experimental observations of heterogeneity, providing predictive insights into how modulating adhesion and motility may modify invasive behavior.

DOI: https://doi.org/10.1371/journal.pcbi.1014747
iScience. 2026 Sep 18. 29(9): 117009

Extracellular matrix composition and stiffness regulates progesterone responsiveness and decidualization.

Danielle Klunk, Laura Homewood, Daniel Abebayehu.

  Endometrial disorders impact the uterine lining and can promote ectopic endometrial tissue growth. A key feature of endometrial disorders is unresponsiveness to hormonal treatments due to progesterone resistance. Because endometrial lesions are found within fibrotic extracellular matrix (ECM), we hypothesized that ECM stiffness and composition regulate progesterone responses. We used hydrogels to mimic physiological stiffnesses and examine how mechanical and biochemical ECM cues influence progesterone-induced differentiation (decidualization) in healthy fibroblasts. We determined that ECM ligands modulate decidualization, with laminin slowing secretory responses in favor of stabilizing upstream FOXO1 and WNT4 signaling, while fibronectin produces quicker but less stable differentiation. Stiff matrices override these ECM cues and inhibit decidualization across ligands. Furthermore, these findings mirror activity in endometriotic lesions, with lesions across the stiffest sites displaying greater fibronectin expression and lower decidualization. Altogether, these data demonstrate a role for the lesion microenvironment in the mechanism of inhibited decidualization and progesterone responses.

Keywords:  ECM; endometrium; fibroblasts; matrix biology; progesterone responsiveness

DOI:  https://doi.org/10.1016/j.isci.2026.117009
Commun Biol. 2026 Sep 08. pii: 1180. [Epub ahead of print]9(1):

Cell-body curvature reduces stall frequency to enhance Vibrio cholerae swimming and chemotaxis through hydrogels.

Marwan Malik, Ziyang Chen, Andrew G T Pyo, Zemer Gitai, Ned S Wingreen, Marianne Grognot.

The swimming motility of the bacterial pathogen Vibrio cholerae is a virulence factor that aids in breaching the mucus layer. V. cholerae has a curved cell shape, and previous work demonstrated that loss of curvature decreases infectivity. Here, we investigate the mechanism by which curvature affects single-cell motility. We compared the chemotactic performance of wild-type curved cells and straight mutants. The two exhibit similar swimming properties in liquid and viscous solutions but differ significantly in mucus-mimicking hydrogels, where curved cells demonstrate an 86% increase in chemotactic drift. Trajectory analysis indicates comparable swimming speeds, but straight mutants experience more frequent stalls, reducing total swimming time. Stalls further reduce chemotactic performance by imposing an average reorientation down the chemical gradient, regardless of cell shape. Coarse-grained molecular dynamics simulations corroborate these results across intestinal mucus hydrogel stiffnesses and identify an optimal curvature for movement through hydrogel-like meshes, close to the pathogen's median curvature. These findings highlight cell shape's role in pathogenicity and the need to study bacterial behaviors under conditions more closely mimicking the host environment.

DOI: https://doi.org/10.1038/s42003-026-10883-9
Colloids Surf B Biointerfaces. 2026 Sep 08. pii: S0927-7765(26)00756-3. [Epub ahead of print]269 116168

Spatiotemporal modeling of focal adhesion growth on viscoelastic substrate.

Yiwan Sun, Xiao Yan, Shaomei Zhu, Zixin Zhu, Xianchao Wang, Zhibo Pu, Qingyun Xie, Xue Gou.

  Focal adhesions (FAs) serve as key structures that mediate the transmission of mechanical forces between cells and the extracellular matrix (ECM). Recent in vitro studies have indicated that ECM viscoelasticity significantly regulates FA growth. However, the regulatory role of viscoelasticity in FA growth and its underlying spatiotemporal mechanisms remain incompletely understood. Herein, by integrating integrin internalization into the classical molecular clutch model, we systematically investigated how ECM viscoelastic parameters (additional stiffness ka, long-term stiffness kl, and viscosity η) affect FA growth. Theoretical results demonstrate that FA length increases sigmoidally with increasing ka and kl, rising from 0.2 μm to 2.9 μm as ka increases from 0.01 to 100 pN/nm, and from 0.5 μm to 2.6 μm as kl increases over the same range. This trend is consistent with existing experimental observations. In addition, the influence of η on FA exhibits stiffness dependence. On soft substrate, FA length increases from 0.5 μm to 2.5 μm as η decreases from 100 pN·s/nm to 0.1 pN·s/nm. Conversely, FA length becomes insensitive to η on stiff substrate. The macroscopic trends of cell adhesion experiments performed on four specific substrates are consistent with the model predictions, providing qualitative support for these model predictions. These results deepen our understanding of the effects of substrate viscoelasticity on FA growth and provides a certain theoretical foundation for the rational design of biomaterials with tailored cell-mechanical crosstalk.

Keywords:  Cell adhesion mechanics; ECM viscoelasticity; Focal adhesion; Integrins internalization; Molecular clutch

DOI:  https://doi.org/10.1016/j.colsurfb.2026.116168
NPJ Precis Oncol. 2026 Sep 05. pii: 343. [Epub ahead of print]10(1):

A pancreatic cancer organoid-macrophage co-culture using starPEG-heparin hydrogel deciphers tumor-immune cell interactions.

Julius Thyen, Victor A Sioson, Daniel Haak, Beatrix Jahnke, Maximilian Fusenig, Abdul M Aftab, Antonia Stammberger, Sascha Brückmann, Heike Polster, Stefanie Hübner, Verena J Kast, Manuel Pfeifer, Rebecca Prause, Vivian Mittné, Carolin Beer, Malin H Reinhart, Adrian M Seifert, Lena Seifert, Martin Bornhäuser, Carsten Werner, Marc Schmitz, Daniela E Aust, Jürgen Weitz, Daniela Loessner, Daniel E Stange, Anna R Poetsch, Mathieu Pecqueux, Franziska Baenke.

Macrophages are among the most abundant immune cells in the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) and play a key role in regulating the immunosuppressive niche that facilitates tumor growth. Although recent three-dimensional (3D) culture systems using patient-derived materials have advanced our understanding of tumor biology, most models lack key cellular TME components and thus fail to capture tumor-immune cell interactions. To address this gap, we developed an in-vitro 3D co-culture model incorporating PDAC patient-derived organoids (PDOs) and macrophages within a synthetic hydrogel matrix. We optimized culture conditions by tuning medium and matrix conditions to support both cell lineages. Flow cytometry and transcriptomic analyses revealed that initially undifferentiated macrophages adopt an M2-like profile upon exposure to PDAC PDOs in starPEG-heparin hydrogels, mirroring the macrophage phenotypes observed by multiplex immunohistochemistry in the matched primary PDAC tissues. Cytokine secretome profiling revealed PDO-specific differences, indicating distinct underlying macrophage polarization subtypes. Collectively, our starPEG-heparin hydrogel-based 3D co-culture enables hypothesis-driven and physiologically relevant studies of tumor-macrophage interactions and may advance immune-modulatory treatment strategies in patients with PDAC.

DOI: https://doi.org/10.1038/s41698-026-01678-6
Elife. 2026 Sep 08. pii: RP101088. [Epub ahead of print]13

Centrosome migration and apical membrane formation during epithelial polarization in MDCK cysts.

Po-Kai Wang, Keng-Hui Lin, Tang K Tang.

  Polarization is crucial for the proper functioning of epithelial cells. Early hallmarks include the trafficking and enrichment of polarity molecules to form the apical membrane (AM) or cell-cell junctions, and the apical positioning of the centrosome. However, the dependencies among polarity molecules, AM formation, and centrosome positioning remain poorly understood. When cultured in Matrigel, de novo polarization of a single epithelial cell is often coupled with cytokinesis. During mitotic exit, centrosomes move to the future AM site, raising questions about their role in polarization. We perturbed centrosomes and polarity regulators in Matrigel-cultured cells and manipulated polarity direction using suspension culture to examine the relationships among polarization features. Surprisingly, centrosomal microtubules may not be necessary for centrosome positioning or AM formation, but their absence reduces the efficiency of AM formation. The polarity regulator Par3, rather than AM component trafficking, influences centrosome positioning. In suspension culture, centrosomes migrate in the direction opposite to AM formation. Taken together, our findings define the hierarchical relationships among several polarization features and show that centrosome-based polarity is not universal in epithelial cells, providing new insights into the mechanisms of epithelial polarization.

Keywords:  3D culture; Madin–Darby canine kidney cells; cell biology; centrosome migration; cytokinesis; epithelial polarity; microtubule

DOI:  https://doi.org/10.7554/eLife.101088
ACS Biomater Sci Eng. 2026 Sep 08.

Synergistic Tuning of Pore Architecture and Mechanical Properties in a Biomimetic COL-HA-PVA Hydrogel Directs BMSC Chondrogenesis for Osteochondral Regeneration.

Peng Chen, Wei Lu, Haoyi Wang, Tianhua Liu, Qihong Jiang, Lingchen Yang, Yihe Hu.

  Engineering hydrogels that simultaneously provide interconnected porosity for cell infiltration while delivering appropriate mechanical cues to direct stem cell fate remains a critical challenge in cartilage tissue engineering. Herein, we report a biomimetic COL-HA-PVA hydrogel scaffold with systematically tunable pore sizes (1.2, 1.4, and 1.6 mm) and concomitant mechanical properties, enabling the co-regulation of the structural and biomechanical microenvironment. The 1.2 mm scaffold exhibited the lowest and most stable compressive modulus across the physiologically relevant strain range, providing a compliant mechanical microenvironment that promoted BMSC chondrogenesis, coupled with enhanced surface hydrophilicity due to collagen functionalization. In vitro, this optimized pore architecture significantly promoted goat bone marrow mesenchymal stem cell (gBMSC) adhesion, spreading, and sustained proliferation over 14 days. More importantly, the 1.2 mm scaffold directed robust chondrogenic differentiation, as evidenced by markedly increased expression of the genes and proteins SOX9, COL-II, and aggrecan relative to larger-pore counterparts. Mechanistically, the scaffold activated the integrin β1-FAK-RhoA/ROCK mechanotransduction axis to enhance SOX9-mediated transcription while suppressing osteogenic markers RUNX2 and COL-I. In a caprine model of full-thickness osteochondral defects, the BMSC-laden 1.2 mm scaffold achieved seamless integration with host tissue, progressive subchondral bone regeneration, and formation of proteoglycan-rich hyaline-like cartilage, as confirmed by micro-CT, histological staining, and GAG quantification. This work demonstrates that synergistic tuning of pore architecture and mechanical properties represents a powerful design strategy for directing stem cell-based cartilage regeneration, offering mechanistic insights into scaffold-guided cell fate determination.

Keywords:  BMSC chondrogenesis; biomimetic hydrogel; mechanical cue; mechanotransduction; osteochondral regeneration; pore architecture

DOI:  https://doi.org/10.1021/acsbiomaterials.6c00857