bims-ecemfi Biomed News
on ECM and fibroblasts
Issue of 2025–06–01
eight papers selected by
Badri Narayanan Narasimhan, University of California, San Diego
  1. Designing hydrogel dimensionality to investigate mechanobiology.
  2. Dynamic Hydrogels with Tunable Mechanics for 3D Organoid Derivation.
  3. Cell-guiding microporous hydrogels by photopolymerization-induced phase separation.
  4. 3D hydrogel platform with macromolecular actuators for precisely controlled mechanical forces on cancer cell migration.
  5. Matrix viscoelasticity drives cell cluster formation to counteract cellular senescence.
  6. Label-Free Prediction of Fluorescently Labeled Fibrin Networks.
  7. Engineering Cellular Self-Adhesions Inside 3D Printed Micro-Arches to Enhance Cell:Biomaterial Attachment.
  8. Immunotyping the Tumor Microenvironment Reveals Molecular Heterogeneity for Personalized Immunotherapy in Cancer.
  1. Soft Matter. 2025 May 29.
    Designing hydrogel dimensionality to investigate mechanobiology.
    Marine Luciano, Sylvain Gabriele.
      Hydrogels are indispensable tools for mechanobiology, providing tunable platforms that mimic the complex extracellular matrix and facilitate the study of cell-microenvironment interactions. This review highlights recent advances in the design of hydrogel systems with dimensionality ranging from 2D to 3D, including innovative 2.5D and sandwich configurations, to dissect the role of biophysical cues in cellular behavior and phenotype regulation. Special attention is given to alginate and gelatin methacrylamide (GelMA) hydrogels, which offer unique mechanical and biochemical properties tailored for diverse applications in 3D cell culture. Cutting-edge strategies to dynamically modulate hydrogel stiffness, viscoelasticity, and spatial confinement are discussed, showcasing their impact on cancer progression, stem cell differentiation, and collective cell migration. By integrating advanced hydrogel fabrication methods, including photopolymerization, dual cross-linking, and microfabrication techniques, this review underscores the transformative potential of hydrogels for unraveling the complexities of cellular mechanotransduction in evolving environments. We also explore the clinical potential of engineered hydrogels across applications including tissue regeneration, disease modeling, and controlled drug delivery. Finally, we discussed key challenges in replicating the dynamic mechanical complexity of living tissues and highlight emerging opportunities in the development of smart and adaptive hydrogel systems. Together, these innovations are paving the way toward next-generation biomimetic platforms that bridge fundamental research and translational applications in mechanobiology.
    DOI:  https://doi.org/10.1039/d4sm01458h
  2. Small. 2025 May 28. e2501862
    Dynamic Hydrogels with Tunable Mechanics for 3D Organoid Derivation.
    Xueyong Xie, Xuewen Chen, Jian Zhou, Tiansong Wang, Gen Yang, Fei Han, Zhao Wei.
      The mechanical properties of the hydrogel play a pivotal role in governing the formation and development of 3D organoids in vitro. However, commonly employed natural hydrogels, such as Matrigel and other extracellular matrix (ECM)-derived products, are characterized by ill-defined and complex compositions, resulting in non-tunable mechanical properties. This limitation poses challenges in controlling organoids' developmental trajectory and 3D morphology. Although numerous synthetic hydrogels with well-defined chemical structures have recently been adopted to study organoids by modulating stiffness, advanced research emphasizes the importance of dynamic mechanical cues, such as dynamic stiffness softening and dynamic viscoelasticity, for optimal organoid derivation. These cues are essential for mimicking the dynamic physiological states of organoids during their growth. Despite their potential, the concept of dynamic hydrogels is often used interchangeably, and a systematic review is lacking to clarify this ambiguity. Furthermore, the mechanisms through which dynamic mechanical cues regulate organoid formation have not been thoroughly reported. This review endeavors to summarize and categorize dynamic hydrogels and reveal the effects of dynamic mechanics on organoid derivation. Additionally, the prospects of dynamic hydrogels in organoid derivation are deliberated to promote a more rational design of synthetic hydrogels, guiding organoid derivation and propelling organoid technology in biomedicine.
    Keywords:  3D organoid derivation; dynamic hydrogels; dynamic softening hydrogels; dynamic viscoelastic hydrogels; tunable mechanics
    DOI:  https://doi.org/10.1002/smll.202501862
  3. Nat Commun. 2025 May 27. 16(1): 4923
    Cell-guiding microporous hydrogels by photopolymerization-induced phase separation.
    Monica Z Müller, Margherita Bernero, Chang Xie, Wanwan Qiu, Esteban Oggianu, Lucie Rabut, Thomas C T Michaels, Robert W Style, Ralph Müller, Xiao-Hua Qin.
      Microporous scaffolds facilitate solute transport and cell-material interactions, but materials allowing for spatiotemporally controlled pore formation in aqueous solutions are lacking. Here, we propose cell-guiding microporous hydrogels by photopolymerization-induced phase separation (PIPS) as instructive scaffolding materials for 3D cell culture. We formulate a series of PIPS resins consisting of two ionic polymers (norbornene-functionalized polyvinyl alcohol, dextran sulfate), di-thiol linker and water-soluble photoinitiator. Before PIPS, the polymers are miscible. Upon photocrosslinking, they demix due to the increasing molecular weight and form a microporous hydrogel. The pore size is tunable in the range of 2-40 μm as a function of light intensity, polymer composition and molecular charge. Unlike conventional methods to fabricate porous hydrogels, our PIPS approach allows for in situ light-controlled pore formation in the presence of living cells. We demonstrate that RGD-functionalized microporous hydrogels support high cell viability (>95%), fast cell spreading and 3D morphogenesis. As a proof-of-concept, these hydrogels also enhance the osteogenic differentiation of human mesenchymal stromal cells, matrix mineralization and collagen secretion. Collectively, this study presents a class of cell-guiding microporous hydrogels by PIPS which may find applications in complex tissue engineering.
    DOI:  https://doi.org/10.1038/s41467-025-60113-9
  4. Nat Commun. 2025 May 24. 16(1): 4831
    3D hydrogel platform with macromolecular actuators for precisely controlled mechanical forces on cancer cell migration.
    Bohan Li, Qingyu Fu, Yan Lu, Cheng Chen, Yingshuai Zhao, Yuanfeng Zhao, Minghui Cao, Wei Zhou, Xiaoliang Fan, Xiaoyu Jiang, Peng Zhao, Yijun Zheng.
      Mechanical forces play a critical role in regulating cancer cell behavior, particularly during metastasis. Here we present a three-dimensional hydrogel platform embedded with near-infrared-responsive macromolecular actuators that enable precise mechanical stimulation of specific integrin subtypes in cancer cells. By leveraging this system, we investigate how different force parameters-magnitude, frequency, and duration-affect the migration and invasion of ovarian cancer cell spheroids, focusing on the integrins αvβ3 and αvβ6. We find that mechanical stimulation enhances collective invasion at early stages and triggers a mesenchymal-to-amoeboid transition during later migration, especially when high-frequency, large-amplitude forces disrupt αvβ3-ligand interactions. In contrast, cells engaging αvβ6-through higher-affinity binding-show limited transition under similar conditions. Molecular simulations support these findings by revealing the underlying mechanics of integrin-specific responses. This 3D hydrogel platform provides a powerful tool for studying mechanotransduction in cancer cells and offers potential insights for developing targeted cancer therapies.
    DOI:  https://doi.org/10.1038/s41467-025-60062-3
  5. J Mater Chem B. 2025 May 28.
    Matrix viscoelasticity drives cell cluster formation to counteract cellular senescence.
    Xinying Wang, Limin Song, Jingwen Zhao, Yiling Xiong, Rongrong Jin, Jing He.
      During tissue repair, stress-induced cellular senescence represents a critical factor that impedes the regenerative potential of tissues. While the regulatory effects of matrix viscoelasticity on cellular behavior have been documented, their role and correlated mechanisms underlying cellular senescence remain unclear. In this study, we engineered a viscoelastic gel matrix exhibiting a storage modulus of approximately 3 kPa, with a tunable loss modulus ranging from 0 to 300 Pa by incorporating linear alginate and modulating the compactness of a polyacrylamide-based covalent network. Utilizing a UV-induced senescence model, we observed that increasing the matrix's viscoelasticity from 0 Pa to 300 Pa led to a significant reduction in the proportion of senescent cells, from 90.5% to 22.7%. Furthermore, cells cultured in these matrices exhibited a tendency to form cell aggregation, with the cell populations demonstrating a collective resistance to stresses. This indicated that viscoelastic materials would promote enhanced cellular interactions, thereby strengthening cellular resilience against UV-induced stresses. Furthermore, combined with microarray analysis, it was concluded that the presence of viscoelastic components activated the connexin 43 (Cx43)-modulated gap junction for cluster formation, thereby suppressing the senescence-associated signaling pathways, including Wnt/β-catenin, MAPK, NF-κB, and TGF-β. Additionally, the integrin-cytoskeleton-Yes-associated protein (YAP) signaling axis played an active role in delaying cell aging. These results provide novel insights into the regulatory role of viscoelastic materials in cellular senescence and offer a compelling foundation for the development of advanced biomaterials for tissue repair.
    DOI:  https://doi.org/10.1039/d5tb00174a
  6. Biomater Res. 2025 ;29 0211
    Label-Free Prediction of Fluorescently Labeled Fibrin Networks.
    Sarah Eldeen, Andres Felipe Guerrero Ramirez, Bora Keresteci, Peter D Chang, Elliot L Botvinick.
      While fluorescent labeling has been the standard for visualizing fibers within fibrillar scaffold models of the extracellular matrix (ECM), the use of fluorescent dyes can compromise cell viability and photobleach prematurely. The intricate fibrillar composition of ECM is crucial for its viscoelastic properties, which regulate intracellular signaling and provide structural support for cells. Naturally derived biomaterials such as fibrin and collagen replicate these fibrillar structures, but longitudinal confocal imaging of fibers using fluorescent dyes may impact cell function and photobleach the sample long before termination of the experiment. An alternative technique is reflection confocal microscopy (RCM) that provides high-resolution images of fibers. However, RCM is sensitive to fiber orientation relative to the optical axis, and consequently, many fibers are not detected. We aim to recover these fibers. Here, we propose a deep learning tool for predicting fluorescently labeled optical sections from unlabeled image stacks. Specifically, our model is conditioned to reproduce fluorescent labeling using RCM images at 3 laser wavelengths and a single laser transmission image. The model is implemented using a fully convolutional image-to-image mapping architecture with a hybrid loss function that includes both low-dimensional statistical and high-dimensional structural components. Upon convergence, the proposed method accurately recovers 3-dimensional fibrous architecture without substantial differences in fiber length or fiber count. However, the predicted fibers were slightly wider than original fluorescent labels (0.213 ± 0.009 μm). The model can be implemented on any commercial laser scanning microscope, providing wide use in the study of ECM biology.
    DOI:  https://doi.org/10.34133/bmr.0211
  7. Adv Mater. 2025 May 24. e2502425
    Engineering Cellular Self-Adhesions Inside 3D Printed Micro-Arches to Enhance Cell:Biomaterial Attachment.
    Anamika Singh, Hannah E Kim, Lauren Rawson, Margaret Miao, Daniel J Cohen.
      A cell can bind to itself and form a self-adhesion that can be engineered and harnessed as a new way to adhere cells to engineered materials-a key challenge for biomaterials are demonstrated. Here, a 3D structure smaller is developed than a single cell, that a Self-Adhesion-Tunnel (SAT) is called, that causes cells to wrap around it and bind to themselves. This process is driven through the cadherin proteins that regulate cell-cell adhesion, and it is shown that many of the key elements of a normal cell-cell adhesion are found in self-adhesions. Size and shape of the SAT determine the efficiency of self-adhesion formation, and >90% efficient formation of self-adhesions are observed in both kidney and skin cells per SAT. Self-adhesions can persist for at least 24 hrs and act to stabilize the cell-material interface and reduce migration. Overall, this ability to co-opt the native cell-cell adhesion machinery in cells and use it as an attachment strategy can provide new approaches for soft-tissue implant integration and tissue engineering scaffolds where stable tissue-material interfaces are critical.
    Keywords:  Biomaterials; bioprinting; cell adhesion; nanomaterials; two photon
    DOI:  https://doi.org/10.1002/adma.202502425
  8. Adv Sci (Weinh). 2025 May 28. e2417593
    Immunotyping the Tumor Microenvironment Reveals Molecular Heterogeneity for Personalized Immunotherapy in Cancer.
    Dongqiang Zeng, Yunfang Yu, Wenjun Qiu, Qiyun Ou, Qianqian Mao, Luyang Jiang, Jianhua Wu, Jiani Wu, Huiyan Luo, Peng Luo, Wenchao Gu, Na Huang, Siting Zheng, Shaowei Li, Yonghong Lai, Xiatong Huang, Yiran Fang, Qiongzhi Zhao, Rui Zhou, Huiying Sun, Wei Zhang, Jianping Bin, Yulin Liao, Masami Yamamoto, Tetsuya Tsukamoto, Sachiyo Nomura, Min Shi, Wangjun Liao.
      The tumor microenvironment (TME) significantly influences cancer prognosis and therapeutic outcomes, yet its composition remains highly heterogeneous, and currently, no highly accessible, high-throughput method exists to define it. To address this complexity, the TMEclassifier, a machine-learning tool that classifies cancers into three distinct subtypes: immune Exclusive (IE), immune Suppressive (IS), and immune Activated (IA), is developed. Bulk RNA sequencing categorizes patient samples by TME subtype, and in vivo mouse model validates TME subtype differences and differential responses to immunotherapy. The IE subtype is marked by high stromal cell abundance, associated with aggressive cancer phenotypes. The IS subtype features myeloid-derived suppressor cell infiltration, intensifying immunosuppression. In contrast, the IA subtype, often linked to EBV/MSI, exhibits robust T-cell presence and improved immunotherapy response. Single-cell RNA sequencing is applied to explore TME cellular heterogeneity, and in vivo experiments demonstrate that targeting IL-1 counteracts immunosuppression of IS subtype and markedly improves its responsiveness to immunotherapy. TMEclassifier predictions are validated in this prospective gastric cancer cohort (TIMES-001) and other diverse cohorts. This classifier could effectively stratify patients, guiding personalized immunotherapeutic strategies to enhance precision and overcome resistance.
    Keywords:  IL‐1; cancer; immunotherapy; immunotyping; tumor microenvironment
    DOI:  https://doi.org/10.1002/advs.202417593
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