bims-ecemfi 2026-08-16 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2026–08–16
eleven papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Transient Cytoskeletal Anisotropy Encodes Short-Term Mechanical Memory in Glioblastoma Cells.
N-cadherin peptides modulate integrin-mediated mechanosensing and preserve mesenchymal stem cell phenotype on tunable hydrogels.
Active wetting/de-wetting of focal adhesions on viscoelastic substrates.
MAP Crosslinker Chirality Regulates Macrophage Polarization Through MD-2 Engagement and Enables Tunable Immunomodulation Through Novel Peptide Design.
Beyond the golden rule of polymer network dynamics: Design principles for tissue-mimetic viscoelasticity.
Not all polymers are equal.
Tumor-Mimetic Microenvironment Primes Cancer Stemness and Drug Resistance through Nucleoskeleton-Mediated Chromatin Remodeling.
Spontaneous spatial sorting by cell shape in growing colonies of rod-like bacteria.
Sensitivity analysis to isolate the effects of proteases and protease inhibitors on extracellular matrix turnover.
Nanoscale artificial antigen-presenting cells reveal metabolic interventions modulate clonal composition of CD8+ T cells.
Confinement-driven states and activity-induced escape of semiflexible polymers in soft traps.

Adv Mater. 2026 Aug 08. e74523

Transient Cytoskeletal Anisotropy Encodes Short-Term Mechanical Memory in Glioblastoma Cells.

Clara Gomez-Cruz, Matthieu Gelin, Lucas Pradeau-Phélut, Arrate Muñoz-Barrutia, Sandrine Etienne-Manneville, Daniel Garcia-Gonzalez.

  Cells experience time-varying mechanical cues when navigating complex microenvironments, yet whether and how they retain a short-term memory of recent deformations remains unclear. Here, we show that glioblastoma cells encode such memory through transient cytoskeletal anisotropy. Combining magneto-mechanical actuation, nanoindentation, and selective cytoskeletal perturbations, we find that actin architectures drive opposite mechanical responses: stress fibers stiffen cells under stretch, whereas the actin cortex governs softening under compression. Vimentin intermediate filaments stabilize actin organization under load, preserving these deformation-specific responses. Mechanical actuation aligns both networks, more strongly for actin than vimentin, and this anisotropy persists after unloading. Using a two-step actuation protocol, we show that residual alignment biases the response to a second deformation: cells retain information about prior loading, and this bias decays as the cytoskeleton relaxes, defining a memory window of minutes to tens of minutes. To integrate these observations, we develop a multi-network constitutive model that links cytoskeletal architecture and loading history to cell mechanics, reproducing asymmetric mechanical responses, cytoskeletal reorganization dynamics, and memory effect. These findings show how invasive cancer cells could exploit residual cytoskeletal order to adapt to fluctuating solid stresses and confinement, and identify vimentin-actin coupling and remodeling kinetics as levers to limit that adaptability.

Keywords:  continuum modeling; cytoskeletal remodeling; glioblastoma; mechanical memory; mechanobiology

DOI:  https://doi.org/10.1002/adma.74523
Biomater Adv. 2026 Aug 06. pii: S2772-9508(26)00401-2. [Epub ahead of print]189 215102

N-cadherin peptides modulate integrin-mediated mechanosensing and preserve mesenchymal stem cell phenotype on tunable hydrogels.

Matthias Recktenwald, Hayley Jankowski, Tyler Torres, Sabriye Yilmaz, Matthew Lowe, Mohammed M Benmassaoud, Sebastián L Vega.

Mesenchymal stem cells (MSCs) are a clinically relevant cell source for regenerative therapies, but it is difficult to expand them in vitro without losing stemness. Standard culture on supraphysiologically stiff tissue culture plastic activates mechanosensitive signaling linked to osteogenic differentiation and reduced multipotency. Although very soft materials (∼1 kPa) are known to preserve stemness, proliferation decreases in a stiffness-dependent manner, and hydrogels in the 5-30 kPa range promote early osteogenic signaling and loss of stemness through integrin-driven mechanotransduction. Here, we use norbornene-modified hyaluronic acid hydrogels to tune substrate stiffness and peptide presentation for the culture of human MSCs. Increasing RGD concentration on 5-20 kPa hydrogels elevates cell spreading and nuclear localization of the mechanosensitive regulator Yes-associated protein (YAP), demonstrating increased mechanosensing within this physiological stiffness range. Incorporation of the N-cadherin mimetic peptide HAVDI reduces cell spreading, increases circularity, and lowers nuclear YAP ratios within 24 h across these stiffness conditions, and decreases nuclear Runx2 levels over three days, indicating reduced activation of osteogenic-associated transcriptional signaling. Despite this reduced mechanosensing, MSCs proliferate similarly on HAVDI-containing and control hydrogels over two weeks, and cells expanded on HAVDI substrates exhibit improved retention of MSC surface marker profiles, including higher CD73 positivity and fewer cells expressing non-MSC-associated markers compared to tissue culture plastic. Together, these results identify a peptide-functionalized hydrogel platform that combines integrin and N-cadherin cues to modulate integrin-associated mechanosensing while supporting MSC expansion.

DOI: https://doi.org/10.1016/j.bioadv.2026.215102
Adv Colloid Interface Sci. 2026 Aug 03. pii: S0001-8686(26)00231-9. [Epub ahead of print]357 104006

Active wetting/de-wetting of focal adhesions on viscoelastic substrates.

Ivana Pajic-Lijakovic, Milan Milivojevic, Boris Martinac, Massimo Vassalli, Peter V E McClintock.

  Cell adhesion to viscoelastic substrates is mediated by focal adhesions (FAs), which dynamically couple actomyosin contractility to the extracellular matrix. Although substrate stress relaxation is known to regulate adhesion stability and cell migration, a predictive physical framework linking viscoelasticity to force transmission and adhesion dynamics remains lacking. Here we review briefly what is known about the active wetting and de-wetting of FAs on viscoelastic substrates and synthesize existing experimental and theoretical work into a two-timescale physical framework to describe the phenomena reported. At short timescales, oscillatory actomyosin-driven displacements are transmitted through molecular clutches, leading to frequency-dependent energy transfer to the substrate. We show that this transfer is maximized at an optimal frequency set by a balance between elastic energy storage and viscous dissipation, establishing a resonance-like mechanism that selects both the effective FA stiffness and traction force amplitude. At longer timescales, this mechanically optimal state couples to adhesion remodelling through an effective surface tension, enabling FA growth and disassembly to be interpreted as active wetting and de-wetting processes. The model predicts that adhesion stability and steady-state size are controlled by substrate stiffness and viscoelastic timescales, as well as mechanosensitive feedback mediated by Piezo1-dependent calcium signalling.

Keywords:  Actomyosin oscillations; Cohesion of focal adhesions; Integrin-ligand adhesion; Molecular clutches substrate viscoelasticity

DOI:  https://doi.org/10.1016/j.cis.2026.104006
Adv Healthc Mater. 2026 Aug 13. e71572

MAP Crosslinker Chirality Regulates Macrophage Polarization Through MD-2 Engagement and Enables Tunable Immunomodulation Through Novel Peptide Design.

Alejandra Suarez-Arnedo, Jeremy L Thomas, Yining Liu, Pablo Cordero-Alvarado, Amy Kim, April Chavez Espinoza, Leica Harvey, Koravit Poysungnoen, Fayanne Lin, Zhiyou Ye, Tatiana Segura.

  Microporous annealed particle (MAP) scaffolds are injectable hydrogel biomaterials that promote tissue regeneration by enabling rapid cell infiltration and presenting reparative cues. Previous work showed that substituting L- with D-chiral residues in matrix metalloproteinase (MMP)-degradable crosslinkers induces adaptive immune-mediated skin regeneration and balanced macrophage responses in vivo, but the underlying mechanisms remain unclear. Here, we identify myeloid differentiation factor 2 (MD-2)-associated TLR4 signaling as a key mechanistic contributor to macrophage polarization driven by crosslinker chirality in MAP scaffolds. Macrophages cultured in D-chiral MAP (DMAP) scaffolds exhibited reduced iNOS, CD86, and TNF-α expression and shifted from an M1-like state toward M0-like phenotypes compared to L-chiral MAP (LMAP) and 2D controls. Competitive inhibition with soluble D-chiral MMP crosslinker peptide (DMMP) partially restored M1 activation, implicating direct peptide-macrophage interactions. Docking and surface plasmon resonance (SPR) analyses revealed higher-affinity binding of DMMP to MD-2 relative to L-chiral peptides. Accordingly, DMAP altered TLR4/MD-2 trafficking and attenuated endocytosis-dependent signaling. Engineering a second D-peptide crosslinker with enhanced MD-2 affinity (DMMP2) reduced inflammatory markers and promoted regenerative macrophage polarization. Together, these results establish peptide chirality as a tunable design parameter for modulating TLR4/MD-2 signaling and engineering immunomodulatory MAP scaffolds.

Keywords:  MAP scaffolds; TLR4/MD‐2 signaling; chirality; immunomodulation; macrophage polarization; peptide crosslinkers; regeneration

DOI:  https://doi.org/10.1002/adhm.71572
Sci Adv. 2026 Aug 14. 12(33): eaeg8172

Beyond the golden rule of polymer network dynamics: Design principles for tissue-mimetic viscoelasticity.

Emilie A Moses, Claire J Wang, Joseph Collins, Jessica Garcia, Josiah H Marshall, Andrey V Dobrynin, Sergei S Sheiko.

Technologies ranging from transportation to biomedical devices rely on soft materials whose performance hinges on balancing stiffness and damping. In conventional polymer networks, however, these properties are typically coupled: Softer materials are intrinsically more dissipative, reflecting a long-standing correlation in polymer dynamics that severely restricts the accessible design space. Here, we move beyond this longstanding constraint using brush-like polymer networks whose architecture in combination with chemistry governs viscoelastic response. By independently tuning strand volume and flexibility, we vary the elastic modulus over orders of magnitude while maintaining nearly constant relaxation time without altering network chemistry. Our findings establish a general framework for encoding viscoelastic responses in polymer networks, enabling the design of tissue-mimetic materials with programmable equilibrium stiffness and rate-dependent dissipation.

DOI: https://doi.org/10.1126/sciadv.aeg8172
FEBS J. 2026 Aug 12.

Not all polymers are equal.

Daniel Yan, Jackson Guo, Yun Chen.

  The effects of extracellular fluid viscosity on cell behavior are increasingly appreciated. Smith et al. observed that cells respond differently to two polymers that generate identical fluid viscosity, suggesting that molecular origins of viscosity shape cellular behavior. One possible explanation is that differences in interpolymer interaction arising from a polymer's charge distribution produce Newtonian vs Non-Newtonian rheology, thereby changing the interactions with cell membrane and contributing to distinct cellular responses.

Keywords:  cell migration; extracellular fluid viscosity; mechanobiology; polymer rheology

DOI:  https://doi.org/10.1111/febs.70692
ACS Appl Mater Interfaces. 2026 Jul 30.

Tumor-Mimetic Microenvironment Primes Cancer Stemness and Drug Resistance through Nucleoskeleton-Mediated Chromatin Remodeling.

Duoduo Zhang, Yung-Chiang Liu, Chunchan Li, Yanshan Xu, Yang Cao, Yin Liu, Xingjian Liu, Yuyan Hua, Peng-Yuan Wang.

  The tumor microenvironment (TME) critically regulates cancer progression by providing biochemical and biophysical cues that shape cellular behavior. However, how defined physical microenvironments govern cancer stemness and chemoresistance through mechanotransduction remains poorly understood. Here, we systematically engineered eight tumor-mimetic microenvironments by integrating serum, oxygen, and 3D compacted culture to investigate their effects on A549 non-small cell lung cancer cells. Among all conditions, cells cultured under 3D culture (PM4C) exhibited reduced cellular stiffness, enhanced expression of cancer stemness markers (EpCAM and CD44), and significantly increased resistance to cisplatin in both in vitro and nude mouse xenograft models. Transcriptomic analysis revealed that differentially expressed genes in the PM4C group were predominantly enriched in cell adhesion, mechanotransduction, stemness, and cisplatin resistance pathways. Metabolomic profiling further revealed a substantial accumulation of anaerobic metabolites associated with the maintenance of stemness. Mechanistically, the PM4C microenvironment remodeled matrix production, cell-ECM interactions, and cytoskeletal organization while inducing epigenetic reprogramming (reduced H3K9 acetylation), collectively promoting a stem-like and chemoresistant phenotype. These findings establish a direct mechanistic link between TME and cancer cell stemness, demonstrating that TME can reprogram stemness and drug responsiveness through mechano-epigenetic regulation. This work provides a mechanobiological framework for engineering physiologically relevant tumor organoids and offers new strategies for developing TME-targeted drugs and therapies.

Keywords:  chromatin remodeling; cytoskeleton; mechanotransduction; nucleoskeleton; tumor microenvironment

DOI:  https://doi.org/10.1021/acsami.6c06355
Soft Matter. 2026 Aug 10.

Spontaneous spatial sorting by cell shape in growing colonies of rod-like bacteria.

Mateusz Ratman, Jimmy Gonzalez Nuñez, Daniel A Beller.

Mechanical interactions among cells in a growing microbial colony can significantly influence the colony's spatial genetic structure and, thus, evolutionary outcomes such as the fates of rare mutations. Here, we computationally investigate how this spatial genetic structure changes as a result of heritable phenotypic variations in cell shape. By modeling rod-like bacterial cells as lengthening and dividing pill-shaped, rigid objects in a 2D overdamped molecular dynamics framework, we simulate the growth of a colony containing two populations with different aspect ratios. Compared to monodisperse colonies, such bidisperse colonies exhibit diminished intermixing between sub-populations when the less elongated cells are too short to nematically order, instead forming large clusters. We find that the cells with longer aspect ratio gradually segregate to the colony periphery. We present evidence that this demixing is related to nematic order in the bulk and to active nematic mixing dynamics near the periphery. These findings are qualitatively robust across different growth rate protocols and initial conditions. Because the periphery is often an advantageous position when nutrients are limited, our results suggest a possible evolutionary selective pressure of mechanical origin that favors large cell aspect ratio.

DOI: https://doi.org/10.1039/d5sm01256b
Biochem Biophys Res Commun. 2026 Aug 12. pii: S0006-291X(26)01156-3. [Epub ahead of print]833 154392

Sensitivity analysis to isolate the effects of proteases and protease inhibitors on extracellular matrix turnover.

Amirreza Yeganegi, Karla Robles, William J Richardson.

  Matrix metalloproteinases (MMPs) are a family of proteases that drive degradation of extracellular matrix (ECM) across many tissues. MMP activity is antagonized by tissue inhibitors of metalloproteinases (TIMPs), resulting in a complex multivariate system with many MMP isoforms and TIMP isoforms interacting across a network of biochemical reactions - each with their own distinct kinetic rates. This system complexity makes it very difficult to identify which specific molecules are most responsible for driving ECM turnover in vivo and therefore the most promising therapeutic targets. To help elucidate the specific roles of various MMP and TIMP isoforms, we present a computational systems biology model of collagen turnover capturing all possible interactions between type I collagen, four different MMP isoforms (MMP-1, -2, -8, and -9), and three different TIMP isoforms (TIMP-1, -2, and -4). We used dye-quenched fluorescent collagen to monitor the degradation of collagen in the presence of various MMP + TIMP cocktails, and we then used these experimental data to fit hypothetical reaction system topologies in order to investigate their respective accuracies. We determined kinetic rate constants for this system and used post-myocardial infarct time courses of collagen, MMP, and TIMP levels to perform a parameter sensitivity analysis across the model reaction rates and predict which molecules and interactions are the important regulators of ECM in the infarcted heart. Notably, the model suggested that MMP degradation and inactivation terms were more important for driving collagen levels than TIMP interaction terms. In sum, this work highlights the need for systems-level analyses to distinguish the roles of various biomolecules operating with a complex system, prioritizes therapeutic targets for post-infarct cardiac remodeling, and presents a computational framework that can be applied to many other collagen-rich tissues.

Keywords:  Collagen turnover; Extracellular matrix; Myocardial infarct; Network model; Protease

DOI:  https://doi.org/10.1016/j.bbrc.2026.154392
Cell Biomater. 2026 Jul 21. pii: 100368. [Epub ahead of print]2(7):

Nanoscale artificial antigen-presenting cells reveal metabolic interventions modulate clonal composition of CD8+ T cells.

Joseph Choy, Sydney R Shannon, Yicheng Zhang, Si-Sim Kang, Yining Zhu, Kenneth M Adusei, Shaelyn R Marx, Milan Patel, Benjamin A Biggs, Hai-Quan Mao, Jonathan P Schneck.

  In response to pathogens, CD8+ T cells reprogram their metabolism to fuel a proliferative burst of antigen-specific T cells. Engineering metabolism can augment CD8+ T cell responses, yet mechanistic studies understanding the direct impact of metabolic programming on T cell phenotype and TCR receptor (TCR) repertoire selection remains unknown. Here, using nanoparticle-based artificial antigen presentation cells (aAPCs) as a model of endogenous expansion to stimulate primary murine CD8+ T cells, we show that glutamine antagonism modulates epitope-specific T cell phenotype by upregulating self-renewal markers and serves a new function as a "clonal filter," enriching high-affinity CD8+ T-cell clones. Moreover, the effect of glutamine inhibition skews towards cells with high-affinity TCRs and enhances their ability to kill in vivo. Collectively, these findings introduce metabolic blockade as a rapid, non-genetic strategy to pre-select durable, high-affinity T cells, providing an easily implementable add-on for adoptive cell therapy.

Keywords:  TCR repertoire; aAPC; immunoengineering; immunometabolism; nanomaterials

DOI:  https://doi.org/10.1016/j.celbio.2026.100368
Eur Phys J E Soft Matter. 2026 Aug 09. pii: 71. [Epub ahead of print]49(8):

Confinement-driven states and activity-induced escape of semiflexible polymers in soft traps.

Sandip Roy, Abhishek Chaudhuri, Anil Kumar Dasanna.

We investigate the dynamics of an actively driven semiflexible polymer confined by a soft harmonic potential. Our study is inspired by in-vitro motility assays where cytoskeletal filaments are propelled by motor proteins under controlled confinement. Using coarse-grained simulations that couple polymer elasticity with stochastic motor attachment, detachment, and force generation, we obtain distinct dynamical regimes ranging from fully confined to freely escaping states, separated by a region of intermittent coexistence. The transitions between these regimes are governed by the combined effects of activity, filament stiffness, confinement strength, and motor processivity. Moderate confinement stabilizes compact spiral conformations through a balance between active forcing and bending elasticity. Stronger activity promotes escape. The motion of the center-of-mass of the polymer exhibits diffusive-ballistic-localized crossovers and oscillations characteristic of trapped chiral active Brownian particles. Our results establish a minimal physical framework for understanding how activity and geometric confinement interact to regulate the transport and morphology of active filaments.

DOI: https://doi.org/10.1140/epje/s10189-026-00618-3