bims-ecemfi 2025-09-14 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2025–09–14
eight papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Tumor-Tissue Boundaries as Instructive Interfaces in Breast Cancer Cell Invasion.
Microgel Aspect Ratio Influences Injectable Granular Hydrogel Scaffold Pore Structure and Cellular Invasion for Tissue Repair.
Impact of Mechanical and Architectural Signals in the Tumor Microenvironment on Melanoma.
Confinement, Jamming, and Adhesion in Cancer Cells Dissociating from a Collectively Invading Strand.
Emergent depth-mechanosensing of epithelial collectives regulates cell clustering and dispersal on layered matrices.
Topographic cues regulate collective cell dynamics in curved nano/microgrooved tubular microchannels.
3D Surface-Patterned Hyaluronic Acid Hydrogels: Customizable Platforms for Enhanced Chondrogenic Differentiation and Organized Production of a Specific Hyaline Cartilage Extracellular Matrix.
Aligned Hydrogels with Continuous Gradients for the design of Complex Bioactive Niches.

Adv Sci (Weinh). 2025 Sep 11. e09249

Tumor-Tissue Boundaries as Instructive Interfaces in Breast Cancer Cell Invasion.

Cornelia Clemens, Thomas Zerjatke, Andrine Frank, Hannah Trampert, Nataliia Kotsiuba, Ingmar Glauche, Tilo Pompe.

  The ability of metastatic cancer cells to invade distant tissues requires them to cross a variety of tissue boundaries, each posing distinct structural and biochemical challenges. In particular, the boundary between dense, extracellular matrix (ECM)-rich tumor tissue and surrounding stromal tissue is associated with phenotypic changes in MDA-MB-231 breast cancer cells following transmigration, including increased invasiveness and aggressiveness. It remains unclear whether this transition arises from selective, permissive filtering of pre-existing subpopulations, such as cancer stem cells, or an instructive response of the entire cell population. Here, by combining single-cell migration analysis, heterogeneity analysis of cell proliferation, and computational modeling, it is demonstrated that tumor-tissue boundaries act as instructive interfaces. Using an established 3D fibrillar collagen I matrix model of interfaces, it is shown that all cells can transmigrate the interface with no evidence of selective filtering of subpopulations. Proliferation heterogeneity remains unchanged between transmigrated and non-transmigrated cells, further supporting an instructive mechanism. Simulations confirm that the interface instructively modulates cell behavior. These results indicate that tissue boundaries can reprogram cancer cell phenotypes, representing a potentially targetable mechanism in metastatic progression.

Keywords:  breast cancer cells; cell migration; extracellular matrix interfaces; instructive phenotype switching

DOI:  https://doi.org/10.1002/advs.202509249
Adv Sci (Weinh). 2025 Sep 12. e11513

Microgel Aspect Ratio Influences Injectable Granular Hydrogel Scaffold Pore Structure and Cellular Invasion for Tissue Repair.

Gabriel J Rodriguez-Rivera, Siddharth Sharma, Chima V Maduka, Sara Boyd, Amy R Perry, Nikolas Di Caprio, Lindsay Riley, Connor E Miksch, Daeyeon Lee, Tatiana Segura, David Issadore, Jason A Burdick.

  Granular hydrogels are emerging as an important class of scaffolds for biomedical applications, due to their injectability and pore structure to support cellular infiltration. Past research has primarily focused on spherical microgels, which allows limited control over granular hydrogel pore size and void volume fraction; however, investigation into microgels with higher aspect ratios has allowed even higher porosity. This study explores the impact of hyaluronic acid microgel aspect ratio (ranging from 3 to 5) on granular hydrogel porosity and cellular interactions. Both simulations and experimental results show increased void volume fractions and pore sizes in granular hydrogels formed from rod-like microgels when compared to volume-matched spherical microgels, which results in increased cellular invasion with an endothelial cell spheroid migration assay. Injection of the hydrogels into a confined space alters particle packing and void space, but porosity is still higher when rod-like microgels are used, which results in increased cellular invasion when injected subcutaneously. Finally, the highest aspect ratio microgels are used as injectable granular hydrogels to treat myocardial infarction in rats and show reduced infarct area and enhanced functional outcomes when compared to untreated controls. This work provides further insight into microgel shape considerations for engineered granular hydrogels.

Keywords:  cellular invasion; granular hydrogels; porosity; tissue repair; void fraction

DOI:  https://doi.org/10.1002/advs.202511513
Adv Healthc Mater. 2025 Sep 07. e01759

Impact of Mechanical and Architectural Signals in the Tumor Microenvironment on Melanoma.

Zerin Mahzabin Khan, Alejandro Rossello-Martinez, Michael Mak.

  Compared to sun-exposed melanomas, acral melanomas are genetically diverse and occur in areas with low sun exposure and high mechanical loads. During metastatic growth, melanomas invade from the epidermis to the dermis layers through dense tumor stroma and are exposed to fibrillar collagen architectures and mechanical stresses. However, the role of these signals during acral melanoma pathogenesis is not well understood. In this study, a novel 3D in vitro platform comprising heterogeneous, bundled collagen architectures recapitulates mechanical and architectural signals from the melanoma tumor microenvironment. YUSEEP patient-derived human acral melanoma and B16F10 mouse melanoma single cells and spheroids are embedded in collagen or bundled collagen hydrogels and mechanically compressed to quantitatively profile cellular responses to these cues, including viability, DNA damage and repair, proliferation, invasion, and nuclear and cellular morphologies. Spatial confinement of cells in a microfluidic platform, solid mechanics simulations, and pharmacological inhibition studies lend further mechanistic insights into these cues. Results reveal mechanical compression induces DNA damage and repair, while interactions with bundled collagen promote a malignant, protrusive phenotype. The findings further suggest that actin polymerization and contractility inhibitors may rescue DNA damage and mitigate malignancy upon compression, thereby potentially paving the way for novel therapeutic targets against acral melanomas.

Keywords:  acral melanoma; biophysical signaling; collagen architectures; mechanical compression; mechanobiology; tumor microenvironment; tumor spheroids

DOI:  https://doi.org/10.1002/adhm.202501759
PRX Life. 2025 ;3(1):

Confinement, Jamming, and Adhesion in Cancer Cells Dissociating from a Collectively Invading Strand.

Wei Wang, Robert A Law, Emiliano Perez Ipiña, Konstantinos Konstantopoulos, Brian A Camley.

When cells in a primary tumor work together to invade into nearby tissue, this can lead to cell dissociations-cancer cells breaking off from the invading front-leading to metastasis. What controls the dissociation of cells and whether they break off singly or in small groups? Can this be determined by cell-cell adhesion or chemotactic cues given to cells? We develop a physical model for this question, based on experiments that mimic aspects of cancer cell invasion using microfluidic devices with microchannels of different widths. Experimentally, most dissociation events ("ruptures") involve single cells breaking off, but we observe some ruptures of large groups (~20 cells) in wider channels. The rupture probability is nearly independent of channel width. We recapitulate the experimental results with a phase-field cell motility model by introducing three different cell states (follower, guided, and high-motility "leader" cells) based on their spatial position. These leader cells may explain why single-cell rupture is the universal most probable outcome. Our simulation results show that cell-channel adhesion is necessary for cells in narrow channels to invade, and strong cell-cell adhesion leads to fewer but larger ruptures. Chemotaxis also influences the rupture behavior: Strong chemotaxis strength leads to larger and faster ruptures. Finally, we study the relationship between biological jamming transitions and cell dissociations. Our results suggest unjamming is necessary but not sufficient to create ruptures.

DOI: https://doi.org/10.1103/prxlife.3.013012
Proc Natl Acad Sci U S A. 2025 Sep 16. 122(37): e2423875122

Emergent depth-mechanosensing of epithelial collectives regulates cell clustering and dispersal on layered matrices.

Hongsheng Yu, Amit Pathak.

  During wound healing, tumor growth, and organ formation, epithelial cells migrate and cluster in layered tissue environments. Although cellular mechanosensing of adhered extracellular matrices is now well recognized, it is unclear how deeply cells sense through distant matrix layers. Since single cells can mechanosense stiff basal surfaces through soft hydrogels of <10 μm thickness, here we ask whether cellular collectives can perform such "depth-mechanosensing" through thicker matrix layers. Using a collagen-polyacrylamide double-layer hydrogel, we found that epithelial cell collectives can mechanosense basal substrates at a depth of >100 μm, assessed by cell clustering and collagen deformation. On collagen layers with stiffer basal substrates, cells initially migrate slower while performing higher collagen deformation and stiffening, resulting in reduced dispersal of epithelial clusters. These processes occur in two broad phases: cellular clustering and dynamic collagen deformation, followed by cell migration and dispersal. Using a cell-populated collagen-polyacrylamide computational model, we show that stiffer basal substrates enable higher collagen deformation, which in turn extends the clustering phase of epithelial cells and reduces their dispersal. Disruption of collective collagen deformation, by either α-catenin depletion or myosin-II inhibition, disables the depth-mechanosensitive differences in epithelial responses between soft and stiff basal substrates. These findings suggest that depth-mechanosensing is an emergent property that arises from collective collagen deformation caused by epithelial cell clusters. This work broadens the conventional understanding of epithelial mechanosensing from immediate surfaces to underlying basal matrices, providing insights relevant to tissue contexts with layers of varying stiffness, such as wound healing and tumor invasion.

Keywords:  collagen; epithelial cells; extracellular matrix; mechanobiology; mechanosensing

DOI:  https://doi.org/10.1073/pnas.2423875122
Lab Chip. 2025 Sep 12.

Topographic cues regulate collective cell dynamics in curved nano/microgrooved tubular microchannels.

Tatsuya Matsubara, Chris P Miller, Chanhong Min, Chia-Yi Su, Jong Seob Choi, Chwee Teck Lim, Jude M Phillip, Joon-Wan Kim, Deok-Ho Kim.

Physical properties of the extracellular matrix, such as topography and curvature, regulate collective epithelial behaviors. However, the interplay between these geometric factors on collective migration is not well understood. In this study, we investigate the effects of topographic cues on a curved surface on collective epithelial migration within tubular microchannels with an inner diameter of 100 μm. These tubular microchannels feature circumferential or longitudinal micro- and nano-grooves fabricated by two-photon polymerization three-dimensional printing and micro-molding techniques. Live cell microscopy records the collective migration of GFP-labeled epithelial cells into the microchannel with each topographical design. We utilized a single-cell behavior analysis for the tracked time-dependent cell position data to visualize and quantify complex cell migration. Results show that longitudinal grooves (800 nm and 4 μm) enhanced cell migration, but circumferential grooves did not significantly enhance cell migration. This indicates that curvature rather than topography dominates migration at the microtube scale. These findings provide insights into the interplay between curvature, microscale structure, and cell behaviors and suggest the potential to control cell behaviors by manipulating the structure and topographic cues with their local microenvironments.

DOI: https://doi.org/10.1039/d5lc00368g
ACS Appl Mater Interfaces. 2025 Sep 12.

3D Surface-Patterned Hyaluronic Acid Hydrogels: Customizable Platforms for Enhanced Chondrogenic Differentiation and Organized Production of a Specific Hyaline Cartilage Extracellular Matrix.

Amrita Natarajan, Anjali Sudha, Derrick Dean, Vineeth M Vijayan.

  Surface patterns and topographies play a pivotal role in directing the stem cell fate and extracellular matrix (ECM) organization. Here, we present a cost-effective, 3D printing-assisted template strategy to generate macroscale surface patterns on hyaluronic acid methacrylate (HAMA) hydrogels. Polylactic acid (PLA) templates with honeycomb, rhombohedral, and triangular geometries were fabricated, and free-radically cross-linked HAMA hydrogels were cast and demolded to yield patterned constructs. Based on the rationale that such patterns can approximate aspects of cartilage zonal organization, we hypothesized that these customizable topographies would enhance the chondrogenic differentiation of human bone marrow-derived mesenchymal stem/stromal cells (hBM-MSCs). A comprehensive evaluation was performed using mechanical testing, swelling analysis, biochemical assays (sGAG, collagen content), metabolic activity (Alamar Blue), immunofluorescence staining, and RT-qPCR for chondrogenic (SOX9, COL2A1, ACAN) and hypertrophic (COL10A1) markers. Honeycomb hydrogels exhibited superior stiffness, swelling resistance, and laminin adsorption compared with rhombohedral, triangular, and nonpatterned controls. hBM-MSCs cultured on honeycomb hydrogels in a chondrogenic medium demonstrated enhanced viability, greater sGAG and collagen deposition normalized to DNA content, and robust upregulation of chondrogenic markers, while limiting hypertrophy and dedifferentiation. Immunostaining further confirmed cartilage-specific ECM organization, with spatial alignment and condensation of MSCs on honeycomb topographies, suggesting the activation of mechanotransduction pathways. This work establishes an innovative design principle linking hydrogel macrogeometry to chondrogenic outcomes, addressing a gap in the field where most studies have focused on micro- and nanoscale cues. Although these hydrogels do not fully replicate all four native cartilage zones, the honeycomb topography promoted alignment, condensation, and stratified ECM deposition, recapitulating key aspects of zonal organization. This 3D-printed template-assisted macropatterning strategy provides a cost-effective, reproducible, and scalable method for fabricating biomimetic scaffolds. These surface patterned hydrogels enable controlled differentiation and spatially organized ECM formation, underscoring their promise for cartilage tissue engineering and personalized repair strategies.

Keywords:  3D-printed templates; cartilage tissue engineering; chondrogenesis; honeycomb-patterned hydrogels; patterning; surface engineering

DOI:  https://doi.org/10.1021/acsami.5c16374
Acta Biomater. 2025 Sep 10. pii: S1742-7061(25)00674-9. [Epub ahead of print]

Aligned Hydrogels with Continuous Gradients for the design of Complex Bioactive Niches.

Huaxiang Yang, Qiyuan Song, Yuesheng Huang, Liying Xiao, Gongwen Yang, Qiang Lu.

  Continuous gradient signals play a vital role in maintaining tissue homeostasis and repairing damaged tissues. A challenge remains for biomaterials to design complex continuous gradients similar to the niches in vivo. Here, a simple but effective strategy is developed to introduce continuous gradient cues to aligned hydrogels by regulating the slow diffusion of nanosized aggregates. Beta-sheet enriched silk nanofibers were tuned to shorter nanoaggregates with ultrasonic treatment to change its diffusion activity. The nanoaggregates were arranged into the pre-designed discontinuous gradient patterns and incubated for several days to convert to continuous gradients through slow diffusion. The low-voltage electrical field was used to stabilize the gradients, following aligned structure formation. The resulting continuous gradients exhibited flexibility, high controllability, and versatility, enabling the formation of multiple complex gradients. Significantly better bioactivity was achieved for the hydrogels with continuous gradients, superior to that with discontinuous gradients. The rat full-thickness wound model indicated that the hydrogels with continuous SDF-1α gradients accelerated scarless wound healing and functional recovery, confirming the critical roles of the gradients in tissue regeneration. Our present study provides a universal platform to design complex niches with multiple continuous gradients, opening a new path for regenerative medicine and bionic organoids. STATEMENT OF SIGNIFICANCE: Both continuous gradient cues and alignment structures play crucial roles in tissue regeneration. Controlled diffusion behaviors were introduced to silk nanofiber systems with pre-designed discontinuous gradients to construct continuous gradients in the aligned hydrogels after electrical field treatment. The biomimetic hydrogels with alignment structure and flexible continuous gradients achieved improved simulation of complex microenvironment in vitro, which effectively regulated cell behaviors and accelerated tissue regeneration. The present work provides a platform to design bioactive materials and study cell-microenvironment interaction.

Keywords:  Aligned structure; Continuous gradient; Hydrogel; Silk; Tissue engineering

DOI:  https://doi.org/10.1016/j.actbio.2025.09.008