bims-ecemfi 2026-06-28 papers

Acta Biomater. 2026 Jun 26. pii: S1742-7061(26)00428-9. [Epub ahead of print]

Matrix mechanics couple contractility to metabolic adaptation in cancer cells.

Joshua M Toth, Anuja Jaganathan, Ramin Basir, Laurent Pieuchot, Yihui Shen, Cynthia A Reinhart-King, Vivek B Shenoy.

Cells dynamically regulate their morphology, contractility, and metabolism in response to the mechano-chemical properties of their microenvironment. Here, we show matrix stiffness and ligand density jointly govern the bioenergetics of contractile cells through a nonequilibrium active chemo-mechanical model built around a newly introduced cellular metabolic potential. This concept links ATP hydrolysis to mechanosensitive signaling, quantifies the energetic cost of stress fiber assembly, and determines mechanically stable states. The metabolic potential enables quantitative prediction of cell contractility, morphology, and ATP consumption in different stiffness 2D and 3D environments, and we find quantitative agreement with experimental measurements in MDA-MB-231 breast cancer cells. The model further predicts activation of AMPK accompanies increased energetic demands in stiffer microenvironments which we experimentally validate and correlate with increased mitochondrial membrane potential, glucose uptake, and intracellular ATP levels. Together, these findings establish a predictive quantitative framework linking mechanosensitive control of cell shape and contractility to actomyosin-dependent ATP consumption and AMPK-mediated energy replenishment. STATEMENT OF SIGNIFICANCE: While it is well established that extracellular matrix stiffness alters cell shape, contractility, and signaling, how these cues quantitatively integrate with cellular energy homeostasis in diseases such as cancer remains unclear. In this work, we establish a framework connecting extracellular mechanics, actomyosin organization, and intracellular energy regulation into a single energetic principle governing cell behavior. We show that mechanical environments reshape the cellular energy budget, driving cells toward morphologies and contractile states that balance energetic demand with metabolic supply. This perspective reframes mechanotransduction not simply as a signaling cascade, but as a process fundamentally constrained by energy economics, providing new insight into how cancer cells navigate mechanically heterogeneous tissues, with implications for invasion, metastasis, and therapeutic targeting of mechano-metabolic vulnerabilities.

Keywords: Finite element modeling; cell energy regulation; cell morphology; cytoskeletal mechanics; mechanosignaling; metabolism

DOI: https://doi.org/10.1016/j.actbio.2026.06.056

Biomaterials. 2026 Jun 21. pii: S0142-9612(26)00426-6. [Epub ahead of print]335 124402

Physical continuity at biomaterial-ECM interfaces is associated with reduced fibroblast activation and NF-κB signaling.

Alejandra Suarez-Arnedo, Michaela Harris, Calista Robinson, Lindsay Riley, Amy Kim, Lucy Zhang, Brenton D Hoffman, Tatiana Segura.

Fibrotic responses at biomaterial-tissue interfaces limit implant integration and regenerative healing, yet how the interaction between biomaterials and the extracellular matrix (ECM) regulates fibroblast activation remains poorly understood. Granular hydrogels including microporous annealed particle (MAP) scaffolds reduce fibrosis, while chemically and mechanically matched hydrogels do not, suggesting a dominant role for scaffold architecture. To determine how biomaterial architecture influences extracellular matrix (ECM) integration and fibroblast activation, we developed a reductionist in vitro model that integrates collagen type I with either MAP scaffolds or chemically and mechanically matched bulk hydrogels. MAP scaffolds allow collagen infiltration and form physically continuous composites, whereas hydrogels exclude collagen and generate interfacial slip planes. This physical integration stabilizes collagen architecture, limits fibroblast-mediated matrix compaction, suppresses contractility, and attenuates myofibroblast transition. Fibroblasts in mechanically integrated environments exhibit reduced expression and nuclear localization of NF-κB and are enriched for quiescent phenotypes. Together, these findings identify biomaterial-ECM physical continuity as a design principle for limiting fibrotic signaling.

Keywords: Biomaterial–tissue interface; Collagen architecture; Extracellular matrix integration; Fibroblast activation; Granular hydrogels; Matrix mechanics; Microporous annealed particle scaffolds; Myofibroblast differentiation; NF-κB signaling

DOI: https://doi.org/10.1016/j.biomaterials.2026.124402

Acta Biomater. 2026 Jun 24. pii: S1742-7061(26)00407-1. [Epub ahead of print]

Matrix permissiveness regulates 3D confinement of fibroblasts in biosynthetic hydrogel microenvironments.

Indira Priyadarshani Patra, Muthulakshmi Kannan, Saujanya Sabarinath, Shiuly Sarkar, Abhijit Deshpande, Shantanu Pradhan.

The extracellular matrix (ECM) is a major regulator of cellular behavior, fate, and various mechanisms underlying homeostasis, development, and disease. Biophysical and biochemical properties of the ECM are known to affect three-dimensional (3D) cellular behavior and phenotype that regulate a wide range of pathological conditions. Tunable biomimetic hydrogels are extensively employed to investigate cell-matrix interactions in defined 3D microenvironments. However, the dynamics of these interactions in complex coupled multiparametric microenvironments has been relatively less studied. This study aims to provide a framework for correlating cellular and nuclear behavior as a function of specific matrix properties (adhesivity, degradability, porosity, and stiffness) in a biosynthetic hydrogel system with varying crosslinking mechanisms. Poly(ethylene glycol diacrylate)-fibrinogen (PF)-based hydrogels were fabricated with varying crosslinking profiles, resulting in a series of hydrogels with varying matrix properties. NIH3T3 mouse fibroblasts were cultured in 3D and their matrix-associated morphological responses were studied over time. Matrix adhesivity and degradability (collectively termed 'matrix permissiveness') were found to be the most influential parameters regulating cell and nuclear behavior. Cells in permissive matrices displayed high viability, high cell density, increased spreading and protrusivity, and large elongated nuclei. Cells in restrictive matrices displayed reduced viability and lower cell density, rounded morphology, lower spreading, and smaller rounded nuclei. Cell confinement and nuclear confinement determined from various morphological features were correlated to matrix permissiveness. Overall, this study provides insights into regulation of cellular and nuclear behavior through modulation of matrix properties which could be used for future applications in various disease contexts. STATEMENT OF SIGNIFICANCE: Biomimetic engineered hydrogels are commonly used to support three-dimensional (3D) tissue-level behavior to recapitulate various developmental processes and disease states. Specific biophysical and biochemical cues in the engineered microenvironment can be used to control cellular behavior, morphology, and function, thereby providing mechanistic insights into cell-matrix interactions. This study assesses the variations in the cellular and nuclear features of fibroblasts encapsulated in 3D hydrogel matrices with varying crosslinking mechanisms. Our results reveal the combinatorial role of matrix adhesivity and degradability in regulating cellular and nuclear confinement of fibroblasts in 3D restrictive microenvironments. Overall, these matrix guiding principles can be implemented in the future to design tunable biomimetic matrices to modulate cell state, behavior, and function.

Keywords: 3D cell behavior; hydrogel; matrix; microenvironment; morphology

DOI: https://doi.org/10.1016/j.actbio.2026.06.046

FEBS J. 2026 Jun 25.

MMP9 drives cancer invasion by mediating integrin membrane trafficking and stabilization.

Sarbajeet Dutta, Swetlana Ghosh, Sumon Kumar Saha, Soumili Sarkar, Md Asrafuddoza Hazari, Simran Tolani, Shamik Sen.

Matrix stiffening promotes cancer progression by elevating matrix metalloprotease (MMP) activity, thereby enabling extracellular matrix degradation and migration. Yet, the nonproteolytic roles of MMPs in invasion remain less defined. Here, we dissect the proteolytic and nonproteolytic functions of MMP9, a metalloprotease whose expression and secretion increase sharply in highly invasive cancer cells in response to stiffness. We find that MMP9 supports cell spreading and 2D migration through a nonproteolytic mechanism that stabilizes focal adhesions, whereas its proteolytic activity is specifically required for 3D invasion. We further identify two distinct integrin β1 (ITGβ1) binding sites that coordinate these functions: The hemopexin domain drives copackaging and transport of the ITGβ1-MMP9 complex to the cell periphery, while the RGD motif stabilizes ITGβ1 at the membrane before matrix degradation. These findings reveal a spatiotemporal mechanism by which MMP9 integrates adhesion dynamics with matrix remodeling to optimize invasive behavior.

Keywords: MMP9; RGD (Arginylglycylaspartic acid); integrin β1 (ITGβ1); invasion; matrix degradation; nonproteolytic function

DOI: https://doi.org/10.1111/febs.70633

J Biomed Mater Res A. 2026 Jul;114(7): e70111

Substrate Stiffness and Viscoelasticity Influence Fibroblast Senescence.

Mackenzie L Skelton, Tanvi Bhat, Ethan Yu, Afia Ofori, Steven R Caliari.

Senescent cell accumulation has been implicated in aging and fibrotic disease, which are both characterized by increased tissue stiffness. However, the direct connection between tissue mechanics and senescence induction remains disputed in the literature. Thus, this work investigates the influence of hydrogel stiffness and viscoelasticity in promoting fibroblast senescence directly and in combination with genotoxic stress. We show that while lung fibroblast YAP/TAZ signaling declines with senescence induction, senescent fibroblasts maintain their mechanosensing capabilities with increased YAP/TAZ nuclear localization on higher stiffness hydrogels. Most notably, we find a unique role for hydrogel viscoelasticity in senescence induction, with soft (2 kPa) viscoelastic substrates promoting both the onset and amplification of senescence, even in the absence of genotoxic stress. These changes are not associated with a decline in YAP/TAZ activity, but instead with a decline in nuclear DAPI intensity, suggesting a role of nuclear organization in driving this phenotype. Overall, this work highlights the influence of mechanics, and viscoelasticity in particular, on the induction of fibroblast senescence.

Keywords: hydrogels; mechanobiology; senescence; viscoelasticity

DOI: https://doi.org/10.1002/jbm.a.70111

Acta Pharmacol Sin. 2026 Jun 22.

Sweetening the bonds: how O-GlcNAcylation modulates cell adhesion.

Wen-Hui Lou, Guo-Hong Qiao, Zi-Jun Wei, Yu-Qin Hu, Yang Li, Qi-Jie Zhao, Shi-Sheng Zhou, Yue Wang, Bei Chen, Zhi-Wei Xu, Xiang Chen.

O-GlcNAcylation is a dynamic, reversible post-translational modification that attaches N-acetylglucosamine (GlcNAc) to the serine or threonine residues of intracellular proteins. Catalysed by O-GlcNAc transferase and removed by O-GlcNAcase, this modification acts as a key nutrient and stress sensor. Although cell adhesion is fundamental to tissue architecture and mechanotransduction, emerging evidence has shown that O-GlcNAcylation profoundly orchestrates these processes. By modulating the composition and signalling of adhesion complexes, O-GlcNAcylation regulates both cell-cell and cell-matrix interactions. Through crosstalk with phosphorylation, this modification drives cellular adhesion plasticity, with broad implications for development, immunity, and diseases, such as cancer and neurodegeneration. Recent advances revealed that O-GlcNAcylation fine-tunes key regulators, including Focal Adhesion Kinase (FAK), Zyxin, and integrins, to control focal adhesion turnover. These mechanistic insights pave the way for novel therapeutic strategies targeting glycosylation-dependent adhesion signalling.

Keywords: ECM; O-GlcNAc; adhesion; cancer; integrin

DOI: https://doi.org/10.1038/s41401-026-01844-3

Acta Biomater. 2026 Jun 20. pii: S1742-7061(26)00395-8. [Epub ahead of print]

A computationally efficient fibril-scale finite element model bridges molecular mechanisms and collagen fibril nonlinearity and failure.

Xiwen Dai, Richard Leslie Abel, Ulrich Hansen, Soraia Pimenta.

Collagen fibrils control the mechanical integrity of many load-bearing tissues, but experimentally isolating how cross-link class, density, and spatial organization regulate fibril nonlinearity and failure remains difficult. This limits mechanistic interpretation of aging- and diabetes-associated changes in collagenous tissue mechanics. Here we present a computationally efficient fibril-scale finite element (FE) framework for large-deformation tension of type I collagen fibrils. The model explicitly represents tropocollagen molecule (TCM) backbones, stochastic cross-link networks, and friction-mediated intermolecular sliding, with constitutive laws calibrated from molecular simulations. The framework enables length-converged ensemble simulations at experimentally relevant single-fibril scales. The model is benchmarked against two independent tensile datasets, reproducing the nonlinear response of human patellar tendon fibrils and capturing the leading stiffness and strength trends induced by methylglyoxal (MG)-treatment in rat Achilles tendon fibrils. Parametric studies show that cross-link density elevates the high-strain tangent modulus and ultimate tensile strength while leaving the low-strain modulus nearly unchanged. Enzymatic maturation has the largest effect at intermediate cross-link density, whereas non-enzymatic cross-links provide weaker stiffening and promote earlier microscopic rupture. At fixed mean density, spatial heterogeneity reduces fibril strength and localizes damage, with strength governed by the local minimum of the cross-link density profile. The model therefore provides a scale-bridging structure-property framework for testing how molecular cross-link changes alter fibril-scale mechanics and for supplying damage-aware inputs to higher-level models of collagenous tissues.

Keywords: Collagen fibril; Cross-links; Damage; Finite element model; Nanomechanics

DOI: https://doi.org/10.1016/j.actbio.2026.06.033