bims-ecemfi 2025-03-02 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2025–03–02
seven papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

Biofabrication of Tunable 3D Hydrogel for Investigating the Matrix Stiffness Impact on Breast Cancer Chemotherapy Resistance.
Collective Transitions from Orbiting to Matrix Invasion in 3D Multicellular Spheroids.
Navigating confinement: Mechanotransduction and metabolic adaptation.
Collagen hydrogels with similar polymer content but different microstructure - A comparative analysis of mechanical response.
Synthetic photoresponsive hydrogels enable in situ control over murine intestinal monolayer differentiation and crypt formation.
Mechanical stretch promotes the migration of mesenchymal stem cells via Piezo1/F-actin/YAP axis.
Rapid self-strengthening in double-network hydrogels triggered by bond scission.

ACS Biomater Sci Eng. 2025 Feb 27.

Biofabrication of Tunable 3D Hydrogel for Investigating the Matrix Stiffness Impact on Breast Cancer Chemotherapy Resistance.

Yue Chen, Dan Xue, Di Huang, Xinying Li, Yuyou Duan, Bin Chen.

  Matrix stiffness is a key factor in breast cancer progression, but its impact on cell function and response to treatment is not fully understood. Here, we developed a stiffness-tunable hydrogel-based three-dimensional system that recapitulates the extracellular matrix and physiological properties of human breast cancer in vitro. Adjusting the ratio of GelMA to PEGDA in the hydrogel formulation enabled the fine-tuning of matrix stiffness across a range of 7 to 52 kPa. Utilizing this three-dimensional (3D) hydrogel platform for a breast cancer cell culture has enabled precise functional evaluations. Variations in matrix stiffness resulted in significant changes in the morphology of breast cancer cells after 2 weeks of incubation. The analysis of transcriptomic sequencing revealed that the 3D microenvironment significantly changed the expression of a wide panel of transcriptomic profiles of breast cancer cells in various matrix stiffness. Gene Ontology analysis further suggested that specific biological functions could potentially be linked to the magnitude of the matrix stiffness. According to our findings, extracellular matrix rigidity modulates the sensitivity of breast cancer cells to paclitaxel and adriamycin. Notably, the expression of ABCB1 and YAP1 genes may be upregulated in the 3D culture environment, potentially contributing to the increased drug resistance observed in breast cancer cells. This work aims to establish facile adjustable hydrogels to deepen insights into matrix rigidity effects on breast cancer cells within 3D microenvironments, highlighting the critical role of extracellular matrix stiffness in modulating cell-matrix interactions.

Keywords:  3D; extracellular matrix; hydrogel; matrix stiffness; mechanotransduction

DOI:  https://doi.org/10.1021/acsbiomaterials.4c01636
bioRxiv. 2025 Feb 11. pii: 2025.02.10.636936. [Epub ahead of print]

Collective Transitions from Orbiting to Matrix Invasion in 3D Multicellular Spheroids.

Jiwon Kim, Hyuntae Jeong, Carles Falcó, Alex M Hruska, W Duncan Martinson, Alejandro Marzoratti, Mauricio Araiza, Haiqian Yang, Christian Franck, José A Carrillo, Ming Guo, Ian Y Wong.

Coordinated cell rotation along a curved matrix interface can sculpt epithelial tissues into spherical morphologies. Subsequently, radially-oriented invasion of multicellular strands or branches can occur by local remodeling of the confining matrix. These symmetry-breaking transitions emerge from the dynamic reciprocity between cells and matrix, but remain poorly understood. Here, we show that epithelial cell spheroids collectively transition from circumferential orbiting to radial invasion via bi-directional interactions with the surrounding matrix curvature. Initially, spheroids exhibit an ellipsoidal shape but become rounded as orbiting occurs. However, cells gradually reorient from coordinated rotation towards outward strand invasion due to the accumulation of contractile tractions at discrete sites. Remarkably, the initial ellipsoid morphology predicts subsequent invasion of 2-4 strands roughly aligned with the major axis. We then perturb collective migration using osmotic pressure, showing that orbiting can be arrested and invasion can be reversed. We also investigate coordinated orbiting in "mosaic" spheroids, showing a small fraction of "leader" cells with weakened cell-cell adhesions can impede collective orbiting but still invade into the matrix. Finally, we establish a minimal self-propelled particle model to elucidate how collective orbiting is mediated by the crosstalk of cell-cell and cell-matrix adhesion along a curved boundary. Altogether, this work elucidates how tissue morphogenesis is governed by the interplay of collective behaviors and the local curvature of the cell-matrix, with relevance for embryonic development and tumor progression.

DOI: https://doi.org/10.1101/2025.02.10.636936
Curr Opin Cell Biol. 2025 Feb 24. pii: S0955-0674(25)00025-0. [Epub ahead of print]94 102487

Navigating confinement: Mechanotransduction and metabolic adaptation.

Alice Amitrano, Debanik Choudhury, Konstantinos Konstantopoulos.

Cell migration through confined spaces is a critical process influenced by the complex three-dimensional (3D) architecture of the local microenvironment and the surrounding extracellular matrix (ECM). Cells in vivo experience diverse fluidic signals, such as extracellular fluid viscosity, hydraulic resistance, and shear forces, as well as solid cues, like ECM stiffness and viscoelasticity. These fluidic and solid stressors activate mechanotransduction processes and regulate cell migration. They also drive metabolic reprogramming, dynamically altering glycolysis and oxidative phosphorylation to meet the cell's energy demands in different microenvironments. This review discusses recent advances on the mechanisms of cell migration in confinement and how confinement-induced cellular behavior leads to metabolic reprogramming.

DOI: https://doi.org/10.1016/j.ceb.2025.102487
J Mech Behav Biomed Mater. 2025 Feb 13. pii: S1751-6161(25)00038-4. [Epub ahead of print]166 106922

Collagen hydrogels with similar polymer content but different microstructure - A comparative analysis of mechanical response.

Kim Busenhart, Julie Brun, Håvar Junker, Alexander E Ehret, Alba Marcellan, Edoardo Mazza.

  Understanding the mechanical properties of collagen hydrogels is essential for successful applications in tissue engineering and 3D cell culture. This study compares the mechanical behavior of two collagen hydrogel sheets with similar collagen content but different microstructures. One of the differences is that one gel is isotropic while the other has collagen fibers oriented towards the sheet's plane. Experiments were performed at macro- (uniaxial tension in the sheet plane) and micro-length scale (AFM-based indentation perpendicular to the plane), and a discrete network model was developed to rationalize the observed differences. The experiments showed an order of magnitude difference in the uniaxial stiffness of the two gels. The softer gel exhibited near-incompressible behavior, while the stiffer gel showed a highly contractile response, with Poisson's ratios around 8. Conversely, the apparent modulus from nano-indentation showed an opposite trend, with higher local stiffness for the gel that was softer in uniaxial tests. The computational model represents the material using a network of bi-linear connectors for the fibrous component and a compressible neo-Hookean material for the surrounding water-rich matrix, assumed to form due to interactions between collagen and water. Under the constraint of equal collagen content, model parameters were tuned to reproduce the observed response of both materials, considering the observed differences in fiber diameter. Importantly, the computations indicate that the difference in collagen orientation cannot explain the observed differences between the mechanical responses of the gels. Successful scaling between the two gels depends on the assumption that, due to their crimped initial state individual fibers primarily experience bending rather than tension when the material is stretched. Moreover, high tensile stretch of the fibers is shown to elicit large lateral contraction. Overall, the results demonstrate the wide range of mechanical properties displayed by hydrogels with similar collagen content, which can be rationalized using discrete models representative of their microstructure.

Keywords:  Collagen hydrogels; Discrete network model; Material stiffness and kinematics; Nano-indentation; Uniaxial tensile test

DOI:  https://doi.org/10.1016/j.jmbbm.2025.106922
Adv Funct Mater. 2025 Jan 15. pii: 2413778. [Epub ahead of print]35(3):

Synthetic photoresponsive hydrogels enable in situ control over murine intestinal monolayer differentiation and crypt formation.

Mark W Young, Colter E Oroke, Bruce E Kirkpatrick, Michael R Blatchley, Peter J Dempsey, Kristi S Anseth.

  As a model of the intestinal epithelium, intestinal stem cells (ISCs) have been grown and differentiated as monolayers on materials where stochastic organization of the crypt and villi cells occurs. We developed an allyl sulfide crosslinked photoresponsive hydrogel with a shear modulus of 1.6 kPa and functionalized with GFOGER, Bm-binder peptide ligands for monolayer growth of ISCs. The allyl sulfide chemistry allowed in situ control of mechanics in the presence of growing ISC monolayers, and structured irradiation afforded spatial regulation of the hydrogel properties. Specifically, ISC monolayers grown on 1.6 kPa substrates were in situ softened to 0.29 kPa, using circular patterns 50, 75, and 100 μm in diameter, during differentiation, resulting in control over the size and arrangement of de novo crypts and monolayer cellularity. These photoresponsive materials should prove useful in applications ranging from studying crypt evolution to drug screening and transport across tissues of changing cellular composition.

Keywords:  Allyl Sulfide; Hydrogel; Intestinal stem cell

DOI:  https://doi.org/10.1002/adfm.202413778
Exp Cell Res. 2025 Feb 21. pii: S0014-4827(25)00057-6. [Epub ahead of print]446(1): 114461

Mechanical stretch promotes the migration of mesenchymal stem cells via Piezo1/F-actin/YAP axis.

Ning Ma, Lei Huang, Qianxu Zhou, Xiaomei Zhang, Qing Luo, Guanbin Song.

  Mesenchymal stem cells (MSCs) have self-renewal ability and the potential for multi-directional differentiation, and their clinical application has promising prospects, but improving the migration ability of MSCs in vivo is one of the challenges. We previously determined mechanical stretch at 1 Hz with 10 % strain for 8 h can significantly promote MSC migration, however, the molecular mechanism remains poorly understood. Here, we reported that the expression and activity of yes-associated protein (YAP) are upregulated after mechanical stretch. As a classical inhibitor of the YAP-TEAD activity and YAP protein, the treatment of verteporfin (VP) suppressed mechanical stretch-promoted MSC migration. We also observed F-actin polymerization after mechanical stretch. Next, we used Latrunculin A (Lat A), the most widely used reagent to depolymerize actin filaments, to treat MSCs and we found that Lat A treatment inhibits MSC migration by suppressing YAP expression and activity. In addition, the protein expression of Piezo1 was also upregulated after mechanical stretch. Knockdown of Piezo1 suppressed mechanical stretch-promoted MSC migration by restraining F-actin polymerization. Together, these findings demonstrate the role of Piezo1/F-actin/YAP signaling pathway in MSC migration under mechanical stretch, providing new experimental evidence for an in-depth understanding the mechanobiological mechanism of MSC migration.

Keywords:  F-actin; MSCs; Mechanical stretch; Migration; Piezo1; YAP

DOI:  https://doi.org/10.1016/j.yexcr.2025.114461
Nat Mater. 2025 Feb 26.

Rapid self-strengthening in double-network hydrogels triggered by bond scission.

Zhi Jian Wang, Wei Li, Xueyu Li, Tasuku Nakajima, Michael Rubinstein, Jian Ping Gong.

The scission of chemical bonds in materials can lead to catastrophic failure, with weak bonds typically undermining the materials' strength. Here we demonstrate how weak bonds can be leveraged to achieve self-strengthening in polymer network materials. These weak sacrificial bonds trigger mechanochemical reactions, forming new networks rapidly enough to reinforce the material during deformation and significantly improve crack resistance. This rapid strengthening exhibits strong rate dependence, dictated by the interplay between bond breaking and the kinetics of force-induced network formation. As the network formation is generally applicable to diverse monomers and crosslinkers with different kinetics, a wide range of mechanical properties can be obtained. These findings may inspire the design of tough polymer materials with on-demand, rate-dependent mechanical behaviours through mechanochemistry, broadening their applications across various fields.

DOI: https://doi.org/10.1038/s41563-025-02137-6