bims-ecemfi 2025-11-16 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2025–11–16
ten papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Extracellular Matrix Viscoelasticity Regulates Mammary Branching Morphogenesis.
PEG-Collagen Interpenetrating Networks Support Enhanced Vasculogenic Self-Assembly and Impact Cell-Mediated Remodeling.
Dynamic Regulation of Granular Hydrogels Through Guest-Host Interactions to Spatiotemporally Guide Cellular Migration.
Programmed Cell Death Protein 1 Engagement Impairs Cytoskeletal Forces and Nuclear Mechanotransduction in T Cells.
Regulation of epithelial tissue homeostasis by active transepithelial transport.
Contractile forces direct the chiral swirling of minimal cell collectives.
An Extracellular Matrix-Producing Subset of Cancer-Associated Fibroblasts Drives Chemoresistance in Breast Cancer via SRC Activation and G0S2 Upregulation.
Matrix stiffness modulates YAP-mediated glycolysis and proliferation in human corneal endothelial cells.
A chemoenzymatic reaction-diffusion system with local inhibition and distal activation.
The Paradox of Heme Oxygenase 1: From Cellular Defense to a Tug of War between Cancer Promotion and Prevention.

Adv Sci (Weinh). 2025 Nov 10. e12873

Extracellular Matrix Viscoelasticity Regulates Mammary Branching Morphogenesis.

Daniella I Walter, Juliette W Moore, Abhishek Sharma, Ryan S Stowers.

  Structural and mechanical cues from the extracellular matrix (ECM) regulate tissue morphogenesis. Tissue development has conventionally been studied with ex vivo systems where the mechanical properties of the extracellular environment are either poorly controlled in space and time, lack tunability, or do not mimic ECM mechanics. For these reasons, it remains unknown how matrix stress relaxation rate, a time-dependent mechanical property that influences several cellular processes, regulates mammary branching morphogenesis. Here, the influence of matrix stress relaxation on mammary branching morphogenesis is systematically investigated using 3D alginate-collagen matrices and spheroids of human mammary epithelial cells. Slow stress relaxing matrices enhanced branching, which is accompanied by local collagen fiber alignment, intermittent pulling contractions applied to the ECM, and focal adhesion signaling. On the contrary, it is observed that growing spheroids in fast stress relaxing matrices applied isotropic pushing forces to the ECM. Pharmacological inhibition of both Rac1 and non-muscle myosin II prevented epithelial branch formation, regardless of matrix stress relaxation rate. Interestingly, restricting cellular expansion via increased osmotic pressure is sufficient to impede epithelial branching in slow stress relaxing matrices. This work highlights the importance of stress relaxation in regulating and directing mammary branch elongation.

Keywords:  branch elongation; hydrogel; mechanotransduction; stress relaxation; viscoelasticity

DOI:  https://doi.org/10.1002/advs.202512873
ACS Biomater Sci Eng. 2025 Nov 15.

PEG-Collagen Interpenetrating Networks Support Enhanced Vasculogenic Self-Assembly and Impact Cell-Mediated Remodeling.

Atticus J McCoy, Jordyn S Novick, Irene W Zhang, Darcy L Jew, Andrew J Putnam.

  The biophysical cues of natural and synthetic hydrogels, including stiffness and the rate of cell-mediated degradation, are often tuned to better understand how to form vessel networks in tissue constructs. Interpenetrating networks (IPN) combine the bioactivity and fibrillar architecture of naturally derived hydrogels and the tunability of synthetic hydrogels. We developed a poly(ethylene glycol) (PEG)-collagen (type I) IPN to investigate the interactive effects of stiffness, the rate of proteolytic degradation, and a fibrillar collagen network on the formation of microvascular networks and cell-mediated hydrogel remodeling. Endothelial cells and fibroblasts were encapsulated in the PEG-collagen IPN, wherein the initial stiffness and rate of degradation were controlled by matrix metalloproteinase-sensitive peptide cross-linker concentration and identity, respectively. We found increased vascular network assembly in PEG-collagen IPN hydrogels that were stiff and slowly degrading and decreased cell-mediated stiffening in hydrogels that were soft and more rapidly degrading compared to PEG hydrogels. Collagen in the IPN was rapidly remodeled by the cells. In both PEG-only and IPN conditions, we found that the cells made the hydrogels more viscoelastic over the course of the experiment. To test if these results were due to the bioactivity or fibrillar architecture of collagen, we evaluated materials where collagen was not fully cross-linked or was added as dry-spun fibers. Unlike the IPN, both materials were less supportive of vasculogenic assembly and did not lead to a reduction in cell-mediated stiffening, suggesting that collagen's fibrillar network is important for increasing vasculogenic potential. Taken together, these results highlight the important interactions of matrix stiffness, degradability, and fibrillar architecture in the design of hydrogels to support vascularization.

Keywords:  collagen; interpenetrating networks; poly(ethylene glycol); vasculogenesis

DOI:  https://doi.org/10.1021/acsbiomaterials.5c01285
Adv Sci (Weinh). 2025 Nov 09. e12971

Dynamic Regulation of Granular Hydrogels Through Guest-Host Interactions to Spatiotemporally Guide Cellular Migration.

Keisuke Nakamura, Nikolas Di Caprio, Jonathan T Taasan, Cody O Crosby, Jason A Burdick.

  Cell migration plays a crucial role in the dynamic processes that guide tissue development, regeneration, and repair; yet, developing cell culture platforms that allow control over cell migration in 3D space and time remains a challenge. Here, a strategy is presented using chemically-responsive granular hydrogels to enable dynamic control over 3D cell migration. Dynamic microgels are fabricated via hyaluronic acid crosslinked via reversible guest-host interactions between adamantane (guest) and β-cyclodextrin (host), which swell in the presence of a cytocompatible competitive guest molecule (adamantane carboxylic acid, Ad-COOH) and de-swell when Ad-COOH is removed. When formed into granular hydrogels, the addition of Ad-COOH results in a dynamic porous material with reduced microgel stiffness and increased pore size. Ad-COOH addition also results in the reduction of mesenchymal stromal cell (MSC) migration from embedded aggregates (spheroids); however, MSC migration returns when Ad-COOH is removed. Furthermore, suspension bioprinting of jammed spheroids into dynamic granular hydrogels results in 4D printed constructs with patterned cellular regions (e.g., lines, zigzags, spirals) where cellular egress is controlled over time through the presence of Ad-COOH to create distinct spatiotemporal cellular patterns. This platform offers precise, on-demand modulation of cell migration, enabling new opportunities to fabricate dynamic, complex engineered tissues.

Keywords:  4D bioprinting; granular hydrogels; migration; suspension printing

DOI:  https://doi.org/10.1002/advs.202512971
ACS Nano. 2025 Nov 12.

Programmed Cell Death Protein 1 Engagement Impairs Cytoskeletal Forces and Nuclear Mechanotransduction in T Cells.

Lingzhu Zhao, Guoqing Zhao, Jiaxin Fu, Yan Liu, Jinteng Feng, Guangjian Zhang, Feng Xu, Hui Guo, Min Lin.

  Programmed cell death protein 1 (PD-1) is a critical immune checkpoint that suppresses T cell activation and cytotoxicity, yet its mechanistic role in regulating T cell mechanotransduction remains unclear. Here, we reveal that PD-1 engagement attenuates T cell activation by impairing cytoskeletal force generation and nuclear mechanotransduction in a mechanically defined microenvironment. Using tunable poly(ethylene glycol) (PEG)-based hydrogels that mimic the stiffness of target cells, we show that PD-1 suppresses T cell receptor (TCR)-mediated activation in a stiffness-dependent manner, requiring immobilized ligand presentation. Mechanistically, PD-1 ligation disrupts actin polymerization, reduces traction forces, and prevents nuclear deformation, thereby impairing the nuclear translocation of mechanosensitive transcription factors yes-associated protein (YAP) and nuclear factor 1 of activated T cells (NFAT1). This inhibition is mediated by the dephosphorylation of cofilin, an actin-severing protein that restricts actin assembly and downstream mechanotransduction. Consequently, PD-1 engagement diminishes the cytokine production and effector cytotoxicity of T cells. Pharmacological or genetic restoration of actin polymerization or nuclear transport rescues nuclear YAP/NFAT1 localization and partially restores T cell activation and function. Our findings suggest PD-1 as a mechanical checkpoint that suppresses T cell immunity by dampening cytoskeletal dynamics and nuclear mechanotransduction, offering insights into the biophysical regulation of immune suppression.

Keywords:  PD-1/PD-L1; TCR; YAP/NFAT1; cytoskeleton; immunosuppression

DOI:  https://doi.org/10.1021/acsnano.5c10650
Proc Natl Acad Sci U S A. 2025 Nov 18. 122(46): e2503156122

Regulation of epithelial tissue homeostasis by active transepithelial transport.

Huiqiong Wu, Charlie Duclut, Gregory Arkowitz, Ranjith Chilupuri, Tien Dang, Jacques Prost, Benoit Ladoux, René-Marc Mège.

  Epithelia are intricate tissues whose function is intimately linked to mechanics. While mechanobiology has primarily focused on factors such as cell-generated contractility and mechanical properties of extracellular matrix, a interesting mechanobiological paradigm highlights the role of osmotic and mechanical pressures in shaping epithelial tissues. In our study, we developed an in vitro model of cell-coated microsized hydrogel spheres (MHSs) which allows to decipher the interplay between cellular activities and tissue mechanics. Drastic, isotropic MHS compressions were observed once the epithelia reached confluence. Further studies revealed that the compression was a process independent of cell contractility but rather regulated by active transepithelial fluid flow. Compressive stresses of about 7 kPa are generated by such an active hydraulic mechanism. Tissue homeostasis is then maintained by a fine balance between cell proliferation and extrusion. Our findings demonstrate the critical role of fluid transport in generating mechanical forces within epithelial tissues. Supported by a theoretical mechanohydraulic model, a mechanistic framework for understanding the intricate interplay between cellular processes and tissue mechanics was established. These results challenge traditional views of epithelial tissue mechanics, emphasizing the pivotal influence of osmotic and mechanical pressures in shaping tissues. We anticipate that this study will advance the understanding of epithelial tissue development, the maintenance of homeostasis, and the mechanisms underlying pathological conditions.

Keywords:  active transport; epithelial homeostasis; osmotic pressure; tissue hydraulics; tissue mechanics

DOI:  https://doi.org/10.1073/pnas.2503156122
Proc Natl Acad Sci U S A. 2025 Nov 25. 122(47): e2415028122

Contractile forces direct the chiral swirling of minimal cell collectives.

Ghina Badih, Alexandre Schaeffer, Benoît Vianay, Pauline Smilovici, Laurent Blanchoin, Manuel Théry, Laëtitia Kurzawa.

  Chirality is a conserved biological feature with critical implications in tissue morphogenesis and embryonic development. In culture, multicellular groups exhibit spontaneous chiral symmetry break when moving collectively on micropatterned surfaces. Although several studies have shown that actin network integrity and actomyosin network contractility contribute to the establishment of the chirality of the movement, the role of contractile forces to the directionality of the chiral bias in collectives remains to be elucidated. Here, we studied the contractile forces produced by a minimal collective constituted of a pair of endothelial cells. We first show that cell doublets confined on disk-shaped micropatterns undergo spontaneous and persistent chiral swirling, displaying a mild but robust clockwise bias, as the one observed in bigger collectives. This bias could be amplified or reversed by modulating contractile forces. Traction force measurements revealed that high forces tend to drive counterclockwise rotation whereas low forces rather favor a clockwise rotation. Furthermore, the study of heterotypic doublets indicates that the direction of the rotation is determined by the more contractile cells within the doublets. These results thus revealed that contractile leader cells could drive the chiral motion of minimal collectives.

Keywords:  cell chirality; contractile forces; minimal collective

DOI:  https://doi.org/10.1073/pnas.2415028122
Cancer Res. 2025 Nov 12.

An Extracellular Matrix-Producing Subset of Cancer-Associated Fibroblasts Drives Chemoresistance in Breast Cancer via SRC Activation and G0S2 Upregulation.

Isabella Hofer, Yann Kieffer, Arianna Mencattini, Hugo Croizer, Rana Mhaidly, Stéphanie Descroix, Christophe Le Tourneau, Maud Kamal, Constance Lamy, Claire Bonneau, Paul H Cottu, Anne Vincent-Salomon, Eugenio Martinelli, Fatima Mechta-Grigoriou, Maria Carla Parrini.

Chemotherapy resistance remains a major hurdle for treating patients with triple-negative breast cancer (TNBC). While cancer associated fibroblasts (CAFs) as an overall population have been shown to modulate treatment response, innovative approaches are required to decipher which and how distinct CAF populations drive chemoresistance. Here, by combining analysis of data from TNBC patients with ex vivo modeling using tumor-on-chip (ToC) technology, we identified a specific CAF population, the extracellular matrix-producing myofibroblasts (ECM-myCAFs), that mediated resistance to chemotherapy. The proportion of ECM-myCAFs decreased after chemotherapy in chemo-sensitive patients, but remained unchanged in chemo-resistant patients. In ToC models, primary ECM-myCAFs promoted TNBC cell survival under chemotherapy treatment. Single-cell RNA sequencing, advanced cell imaging, and functional assays showed that ECM-myCAFs activated SRC kinases in TNBC cells, likely through secreted factors and upregulated the apoptosis regulator G0S2. SRC inhibition or G0S2 silencing completely abolished TNBC cell chemoresistance driven by ECM-myCAFs. Altogether, this work reveals the unique role of the specific ECM-myCAF population and identifies G0S2 as a key player in chemoresistance in TNBC.

DOI: https://doi.org/10.1158/0008-5472.CAN-25-0966
Biomater Adv. 2025 Nov 07. pii: S2772-9508(25)00421-2. [Epub ahead of print]180 214594

Matrix stiffness modulates YAP-mediated glycolysis and proliferation in human corneal endothelial cells.

Mingyue Zhong, Jun Zhao, Tingjun Fan.

  Human corneal endothelium (HCE) plays a vital role in preserving corneal transparency and thickness. However, a marked reduction in the cell density can result in functional decompensation, potentially leading to blindness. The scarcity of donor corneas has limited the development of clinical interventions for this condition, therefore, developing highly functional tissue-engineered HCE (TE-HCE) important. The construction of TE-HCE fundamentally relies on modulating the mechanical microenvironment of the scaffold, which is essential for promoting the optimal proliferation and metabolic activity of the seeded cells. In this study, we used polyacrylamide hydrogels with stiffnesses of 25, 50, and 100 kPa to simulate the mechanical properties of Descemet's membranes and explore the regulatory role of matrix stiffness in HCE cell metabolism and proliferation. An increased scaffold stiffness promoted the proliferation of HCE cells by enhancing the mechanical response of HCE cells, increasing the nuclear translocation of Yes-associated protein (YAP), and promoting the expression of downstream proliferation regulatory genes. Increasing the stiffness of the scaffold also enhanced the glycolysis level of HCE cells by promoting the expression of key glycolytic enzymes, thereby improving the viability and energy yield of HCE cells. Notably, the variations in scaffold stiffness could influence cell proliferation via the YAP pathway by modulating the glycolysis levels, potentially establishing the positive feedback of "metabolic response-proliferation." This study elucidates the regulatory mechanisms by which mechanical microenvironments influence cellular functions, and provides a theoretical foundation and technical support for the development of tissue-engineered products with precise mechanical properties.

Keywords:  Cell proliferation; Glycolysis; Metabolic response; Polyacrylamide hydrogel; Tissue-engineered human corneal endothelium

DOI:  https://doi.org/10.1016/j.bioadv.2025.214594
Nat Commun. 2025 Nov 12. 16(1): 9885

A chemoenzymatic reaction-diffusion system with local inhibition and distal activation.

Rishi Ram Mahato, Niranjani Adikessavane, Nandha Kumar Ettikkan, Subhabrata Maiti.

Spatiotemporal gating in signal transduction and corresponding activation or inhibition of a biochemical pathway is the hallmark of biological functionality. Herein, through both experimental and computational approaches, we developed a synthetic system to mimic one of the key biological signaling events - local inhibition and distal (long-range) activation (LIDA). The basis of our system lies in the differential diffusivity of - (i) injected dormant activator or pro-activator (Pro-A, urea, fast to diffuse due to non-binding with nanoparticle (NP) in gel matrix) that converts to activator (A, ammonium bicarbonate) via an enzyme (urease) embedded in the hydrogel) and (ii) inhibitor (IN, adenosine triphosphate (ATP), diffusion restricted due to interaction with NP). Here A and IN act as the activator and inhibitor of a base-catalyzed proton transfer reaction in the gel matrix, respectively. The indispensability of ProA to A conversion during diffusion for efficient time-regulated LIDA effect has also been demonstrated. The ability to input spatial gating of pH and reaction activation can potentially be extrapolated to develop neuromorphic self-assembled systems with distal programmability.

DOI: https://doi.org/10.1038/s41467-025-65605-2
Adv Biol (Weinh). 2025 Nov 14. e00390

The Paradox of Heme Oxygenase 1: From Cellular Defense to a Tug of War between Cancer Promotion and Prevention.

Sidhant Jain, Meenakshi Rana, Nilza Angmo, Neha Vimal.

  The Hmox1 enzyme, which is the inducible enzyme among the Hmoxs, catalyzes the first and rate-limiting step in the heme degradation pathway, generating three byproducts, namely, carbon monoxide, free iron, and biliverdin. These byproducts can affect an array of biological processes; hence, Hmox1 modulates multiple metabolic processes. Along with the degradation of cytotoxic heme, Hmox1 provides protection against inflammation, apoptosis, and oxidative stress. It also ameliorates tissue injury, maintains iron homeostasis, and supports embryonic survival. Initially, different studies labeled it as an active cancer-assisting agent; however, multiple recent studies have shown that it also deters cancer progression. Hence, this review first looks into the traditional role of Hmox1 and various Hmox1 inducers. Second, there are multiple links between Hmox1 and different types of cancer, including how it acts as a promoter or plays an antitumor role in different or even the same cancers. On the basis of the available data, the work proposes a few speculations to explain this dual role of Hmox1 in cancer.

Keywords:  apoptosis; cancer; heme, Hmox1; inflammation; iron

DOI:  https://doi.org/10.1002/adbi.202500390