bims-ecemfi 2025-04-20 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2025–04–20
six papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Protrusion force and cell-cell adhesion-induced polarity alignment govern collective migration modes.
Nuclear Deformation and Stiffness-Dependent Traction Force Generation Dictate the Migration of Cells under Confinement.
Semi-synthetic fibrous fibrin composites promote 3D microvascular assembly, survival, and host integration of endothelial cells without mesenchymal cell support.
Hypertrophic adipocytes increase extracellular vesicle-mediated lipid release and reprogram breast cancer cell metabolism.
Hydrogels with programmed spatiotemporal mechanical cues for stem cell-assisted bone regeneration.
Mechanochemical bistability of intestinal organoids enables robust morphogenesis.

Biophys J. 2025 Apr 14. pii: S0006-3495(25)00237-1. [Epub ahead of print]

Protrusion force and cell-cell adhesion-induced polarity alignment govern collective migration modes.

Huijing Wang, Catalina Ardila, Ajita Jindal, Vaishali Aggarwal, Weikang Wang, Jonathan Vande Geest, Yi Jiang, Jianhua Xing, Shilpa Sant.

Collective migration refers to the coordinated movement of cells as a single unit during migration. While collective migration enhances invasive and metastatic potential in cancer, the mechanisms driving this behavior and regulating tumor migration plasticity remain poorly understood. This study provides a mechanistic model explaining the emergence of different modes of collective migration under hypoxia-induced secretome. We focus on the interplay between cellular protrusion force and cell-cell adhesion using collectively migrating three-dimensional microtumors as models with well-defined microenvironments. Large microtumors show directional migration due to intrinsic hypoxia, while small microtumors exhibit radial migration when exposed to hypoxic secretome. Here, we developed an in silico multi-scale microtumor model (MSMM) based on the cellular Potts model and implemented in CompuCell3D to elucidate underlying mechanisms. We identified distinct migration modes within specific regions of protrusion force and cell-cell adhesion parameter space and studied these modes using in vitro experimental microtumor models. We show that sufficient cellular protrusion force is crucial for radial and directional collective microtumor migration. Radial migration emerges when sufficient cellular protrusion force is generated, driving neighboring cells to move collectively in diverse directions. Within migrating tumors, strong cell-cell adhesion enhances the alignment of cell polarity, breaking the symmetric angular distribution of protrusion forces and leading to directional microtumor migration. The integrated results from the experimental and computational models provide fundamental insights into collective migration in response to different microenvironmental stimuli. Our computational and experimental models can adapt to various scenarios, providing valuable insights into cancer migration mechanisms.

DOI: https://doi.org/10.1016/j.bpj.2025.04.010
ACS Appl Mater Interfaces. 2025 Apr 15.

Nuclear Deformation and Stiffness-Dependent Traction Force Generation Dictate the Migration of Cells under Confinement.

Zheng Wang, Feng Xu, Di Wu, Wei Huang, Zhiqin Chu, Yuan Lin.

  Cells need to migrate through confined spaces during processes such as embryo development and cancer metastasis. However, the fundamental question of how confinement size and surrounding rigidity collectively regulate the migration capability of cells remains unclear. Here, by utilizing maskless photolithography with a digital micromirror device (DMD), a microchannel with precisely controlled width and wall stiffness (similar to those exhibited by natural tissues) is fabricated. We find that increasing the rigidity of the confining wall leads to a more reduced nuclear volume but has no detectable influence on the myosin expression level in the cells. More interestingly, a biphasic trend of the cell speed is observed, with the migration velocity reaching its minimum at an intermediate wall rigidity of ∼10 kPa. A motor-clutch-based pulling race model is then proposed, which suggests that such biphasic dependence is due to the fact that a very soft channel wall will result in small deformation of the nucleus and consequently reduced cell-wall friction, while larger myosin-based crawling force can be triggered by a stiff confining boundary, both leading to a relatively high migration speed. These findings could provide critical insights into novel strategies for controlling the movement of cells and the design of high-performance biological materials.

Keywords:  ECM stiffness; cell migration; confinement; hydrogel printing; nuclear deformation; theoretical model

DOI:  https://doi.org/10.1021/acsami.5c03048
Bioact Mater. 2025 Jul;49 652-669

Semi-synthetic fibrous fibrin composites promote 3D microvascular assembly, survival, and host integration of endothelial cells without mesenchymal cell support.

Firaol S Midekssa, Christopher D Davidson, Megan E Wieger, Jordan L Kamen, Kaylin M Hanna, Danica Kristen P Jayco, Michael M Hu, Nicole E Friend, Andrew J Putnam, Adam S Helms, Ariella Shikanov, Brendon M Baker.

  Vasculogenic assembly of 3D capillary networks remains a promising approach to vascularizing tissue-engineered grafts, a significant outstanding challenge in tissue engineering and regenerative medicine. Current approaches for vasculogenic assembly rely on the inclusion of supporting mesenchymal cells alongside endothelial cells, co-encapsulated within vasculo-conducive materials such as low-density fibrin hydrogels. Here, we established a material-based approach to circumvent the need for supporting mesenchymal cells and report that the inclusion of synthetic matrix fibers in dense (>3 mg mL-1) 3D fibrin hydrogels can enhance vasculogenic assembly in endothelial cell monocultures. Surprisingly, we found that the addition of non-cell-adhesive synthetic matrix fibers compared to cell-adhesive synthetic fibers best encouraged vasculogenic assembly, proliferation, lumenogenesis, a vasculogenic transcriptional program, and additionally promoted cell-matrix interactions and intercellular force transmission. Implanting fiber-reinforced prevascularized constructs to assess graft-host vascular integration, we demonstrate additive effects of enhanced vascular network assembly during in vitro pre-culture, fiber-mediated improvements in endothelial cell survival and vascular maintenance post-implantation, and enhanced host cell infiltration that collectively enabled graft vessel integration with host circulation. This work establishes synthetic matrix fibers as an inexpensive alternative to sourcing and expanding secondary supporting cell types for the prevascularization of tissue constructs.

Keywords:  Cell-ECM interactions; Endothelial cells; Graft-host integration; Hydrogels; Microvasculature; Vasculogenic assembly

DOI:  https://doi.org/10.1016/j.bioactmat.2025.02.029
bioRxiv. 2025 Mar 31. pii: 2025.03.28.645549. [Epub ahead of print]

Hypertrophic adipocytes increase extracellular vesicle-mediated lipid release and reprogram breast cancer cell metabolism.

Garrett F Beeghly, Marlee I Pincus, Rohan R Varshney, Dilip D Giri, Domenick J Falcone, Michael C Rudolph, Marc A Antonyak, Neil M Iyengar, Claudia Fischbach.

Obesity worsens cancer-specific survival and all-cause mortality for women diagnosed with breast cancer. Rich in adipose tissue, the breast exhibits increased adipocyte size in obesity, which correlates with poor prognosis. However, adipocyte size is highly heterogeneous as adipose tissue expands through both hyperplasia and hypertrophy; and adipocyte size can increase independently of weight gain. Despite these observations, the impact of adipocyte size on breast cancer cell behavior remains unclear due to insufficient approaches to isolate adipocytes based on size and maintain them in culture for mechanistic studies. Here, we develop strategies to culture size-sorted adipocytes from two mouse models of obesity and test their functional impact on tumor cell malignancy. We find that large adipocytes are transcriptionally distinct from small adipocytes and are enriched for gene sets related to adipose tissue dysfunction, including altered lipid processing. In coculture studies, large adipocytes promote lipid accumulation in breast cancer cells, and enhance their migration, proliferation, and aerobic metabolism in a manner dependent on fatty acid oxidation. These changes coincide with increased release of extracellular vesicles by large versus small adipocytes, which transfer lipid to recipient tumor cells. Moving forward, our findings suggest that adipocyte size could serve as a prognostic biomarker for women with breast cancer and help identify new therapeutic targets to advance clinical outcomes for these patients.

DOI: https://doi.org/10.1101/2025.03.28.645549
Nat Commun. 2025 Apr 16. 16(1): 3633

Hydrogels with programmed spatiotemporal mechanical cues for stem cell-assisted bone regeneration.

Bin Xue, Zhengyu Xu, Lan Li, Kaiqiang Guo, Jing Mi, Haipeng Wu, Yiran Li, Chunmei Xie, Jing Jin, Juan Xu, Chunping Jiang, Xiaosong Gu, Meng Qin, Qing Jiang, Yi Cao, Wei Wang.

Hydrogels are extensively utilized in stem cell-based tissue regeneration, providing a supportive environment that facilitates cell survival, differentiation, and integration with surrounding tissues. However, designing hydrogels for regenerating hard tissues like bone presents significant challenges. Here, we introduce macroporous hydrogels with spatiotemporally programmed mechanical properties for stem cell-driven bone regeneration. Using liquid-liquid phase separation and interfacial supramolecular self-assembly of protein fibres, the macroporous structure of hydrogels provide ample space to prevent contact inhibition during proliferation. The rigid protein fibre-coated pore shell provides sustained mechanical cues for guiding osteodifferentiation and protecting against mechanical loads. Temporally, the hydrogel exhibits tunable degradation rates that can synchronize with new tissue deposition to some extent. By integrating localized mechanical heterogeneity, macroporous structures, surface chemistry, and regenerative degradability, we demonstrate the efficacy of these stem cell-encapsulated hydrogels in rabbit and porcine models. This marks a substantial advancement in tailoring the mechanical properties of hydrogels for stem cell-assisted tissue regeneration.

DOI: https://doi.org/10.1038/s41467-025-59016-6
Nat Phys. 2025 ;21(4): 608-617

Mechanochemical bistability of intestinal organoids enables robust morphogenesis.

Shi-Lei Xue, Qiutan Yang, Prisca Liberali, Edouard Hannezo.

  Reproducible pattern and form generation during embryogenesis is poorly understood. Intestinal organoid morphogenesis involves a number of mechanochemical regulators such as cell-type-specific cytoskeletal forces and osmotically driven lumen volume changes. It is unclear how these forces are coordinated in time and space to ensure robust morphogenesis. Here we show how mechanosensitive feedback on cytoskeletal tension gives rise to morphological bistability in a minimal model of organoid morphogenesis. In the model, lumen volume changes can impact the epithelial shape via both direct mechanical and indirect mechanosensitive mechanisms. We find that both bulged and budded crypt states are possible and dependent on the history of volume changes. We test key modelling assumptions via biophysical and pharmacological experiments to demonstrate how bistability can explain experimental observations, such as the importance of the timing of lumen shrinkage and robustness of the final morphogenetic state to mechanical perturbations. This suggests that bistability arising from feedback between cellular tensions and fluid pressure could be a general mechanism that coordinates multicellular shape changes in developing systems.

Keywords:  Biological physics; Computational biophysics

DOI:  https://doi.org/10.1038/s41567-025-02792-1