bims-ecemfi 2024-07-21 papers

bims-ecemfi

Biomed News

on ECM and fibroblasts

Issue of 2024‒07‒21
twelve papers selected by
Badri Narayanan Narasimhan, University of California, San Diego

E-cadherin tunes tissue mechanical behavior before and during morphogenetic tissue flows.
Tensile force field plays a crucial role in local invasion of tumor cells through a mechano-chemical coupling mechanism.
Zonal Patterning of Extracellular Matrix and Stromal Cell Populations Along a Perfusable Cellular Microchannel.
Viscoelasticity in 3D Cell Culture and Regenerative Medicine: Measurement Techniques and Biological Relevance.
Using Microfluidics to Align Matrix Architecture and Generate Chemokine Gradients Promotes Directional Branching in a Model of Epithelial Morphogenesis.
Mechanical evolution of metastatic cancer cells in three-dimensional microenvironment.
Free energy calculations for membrane morphological transformations and insights to physical biology and oncology.
Biophysical modeling identifies an optimal hybrid amoeboid-mesenchymal phenotype for maximal T cell migration speeds.
Engineering programmable material-to-cell pathways via synthetic notch receptors to spatially control differentiation in multicellular constructs.
A geometrical theory of gliding motility based on cell shape and surface flow.
Fully synthetic hydrogels promote robust crypt formation in intestinal organoids.
Polyploidy of MDA-MB-231 cells drives increased extravasation with enhanced cell-matrix adhesion.

Curr Biol. 2024 Jul 10. pii: S0960-9822(24)00822-4. [Epub ahead of print]

E-cadherin tunes tissue mechanical behavior before and during morphogenetic tissue flows.

Xun Wang, Christian M Cupo, Sassan Ostvar, Andrew D Countryman, Karen E Kasza.

  Adhesion between epithelial cells enables the remarkable mechanical behavior of epithelial tissues during morphogenesis. However, it remains unclear how cell-cell adhesion influences mechanics in both static and dynamically flowing confluent epithelial tissues. Here, we systematically modulate E-cadherin-mediated adhesion in the Drosophila embryo and study the effects on the mechanical behavior of the germband epithelium before and during dramatic tissue remodeling and flow associated with body axis elongation. Before axis elongation, we find that increasing E-cadherin levels produces tissue comprising more elongated cells and predicted to be more fluid-like, providing reduced resistance to tissue flow. During axis elongation, we find that the dominant effect of E-cadherin is tuning the speed at which cells proceed through rearrangement events. Before and during axis elongation, E-cadherin levels influence patterns of actomyosin-dependent forces, supporting the notion that E-cadherin tunes tissue mechanics in part through effects on actomyosin. Notably, the effects of ∼4-fold changes in E-cadherin levels on overall tissue structure and flow are relatively weak, suggesting that the system is tolerant to changes in absolute E-cadherin levels over this range where an intact tissue is formed. Taken together, these findings reveal dual-and sometimes opposing-roles for E-cadherin-mediated adhesion in controlling tissue structure and dynamics in vivo, which result in unexpected relationships between adhesion and flow in confluent tissues.

Keywords:  E-cadherin; cell-cell adhesion; convergent extension; epithelial morphogenesis; tissue fluidity

DOI:  https://doi.org/10.1016/j.cub.2024.06.038
Soft Matter. 2024 Jul 19.

Tensile force field plays a crucial role in local invasion of tumor cells through a mechano-chemical coupling mechanism.

Jianfeng Meng, Xiangyu Xu, Chaohui Jiang, Peng Xia, Pengfei Xu, Liangfei Tian, Yingke Xu, Dechang Li, Youhua Tan, Baohua Ji.

Cancer metastasis starts from early local invasion, during which tumor cells detach from the primary tumor, penetrate the extracellular matrix (ECM), and then invade neighboring tissues. However, the cellular mechanics in the detaching and penetrating processes have not been fully understood, and the underlying mechanisms that influence cell polarization and migration in the 3D matrix during tumor invasion remain largely unknown. In this study, we employed a dual tumor-spheroid model to investigate the cellular mechanisms of the tumor invasion. Our results revealed that the tensional force field developed by the active contraction of cells and tissues played a pivotal role in tumor invasion, acting as the driving force for remodeling the collagen fibers during the invasion process. The remodeled collagen fibers promoted cell polarization and migration because of the stiffening of the fiber matrix. The aligned fibers facilitated tumor cell invasion and directed migration from one spheroid to the other. Inhibiting/shielding the cellular contractility abolished matrix remodeling and re-alignment and significantly decreased tumor cell invasion. By developing a coarse-grained cell model that considers the mutual interaction between cells and fibers, we predicted the tensional force field in the fiber network and the associated cell polarization and cell-matrix interaction during cell invasion, which revealed a mechano-chemical coupling mechanism at the cellular level of the tumor invasion process. Our study highlights the roles of cellular mechanics at the early stage of tumor metastasis and may provide new therapeutic strategies for cancer therapy.

DOI: https://doi.org/10.1039/d4sm00335g
bioRxiv. 2024 Jul 09. pii: 2024.07.09.602744. [Epub ahead of print]

Zonal Patterning of Extracellular Matrix and Stromal Cell Populations Along a Perfusable Cellular Microchannel.

Brea Chernokal, Bryan J Ferrick, Jason P Gleghorn.

The spatial organization of biophysical and biochemical cues in the extracellular matrix (ECM) in concert with reciprocal cell-cell signaling is vital to tissue patterning during development. However, elucidating the role an individual microenvironmental factor plays using existing in vivo models is difficult due to their inherent complexity. In this work, we have developed a microphysiological system to spatially pattern the biochemical, biophysical, and stromal cell composition of the ECM along an epithelialized 3D microchannel. This technique is adaptable to multiple hydrogel compositions and scalable to the number of zones patterned. We confirmed that the methodology to create distinct zones resulted in a continuous, annealed hydrogel with regional interfaces that did not hinder the transport of soluble molecules. Further, the interface between hydrogel regions did not disrupt microchannel structure, epithelial lumen formation, or media perfusion through an acellular or cellularized microchannel. Finally, we demonstrated spatially patterned tubulogenic sprouting of a continuous epithelial tube into the surrounding hydrogel confined to local regions with stromal cell populations, illustrating spatial control of cell-cell interactions and signaling gradients. This easy-to-use system has wide utility for modeling three-dimensional epithelial and endothelial tissue interactions with heterogeneous hydrogel compositions and/or stromal cell populations to investigate their mechanistic roles during development, homeostasis, or disease.

DOI: https://doi.org/10.1101/2024.07.09.602744
ACS Mater Au. 2024 Jul 10. 4(4): 354-384

Viscoelasticity in 3D Cell Culture and Regenerative Medicine: Measurement Techniques and Biological Relevance.

Payam Eliahoo, Hesam Setayesh, Tyler Hoffman, Yifan Wu, Song Li, Jennifer B Treweek.

The field of mechanobiology is gaining prominence due to recent findings that show cells sense and respond to the mechanical properties of their environment through a process called mechanotransduction. The mechanical properties of cells, cell organelles, and the extracellular matrix are understood to be viscoelastic. Various technologies have been researched and developed for measuring the viscoelasticity of biological materials, which may provide insight into both the cellular mechanisms and the biological functions of mechanotransduction. Here, we explain the concept of viscoelasticity and introduce the major techniques that have been used to measure the viscoelasticity of various soft materials in different length- and timescale frames. The topology of the material undergoing testing, the geometry of the probe, the magnitude of the exerted stress, and the resulting deformation should be carefully considered to choose a proper technique for each application. Lastly, we discuss several applications of viscoelasticity in 3D cell culture and tissue models for regenerative medicine, including organoids, organ-on-a-chip systems, engineered tissue constructs, and tunable viscoelastic hydrogels for 3D bioprinting and cell-based therapies.

DOI: https://doi.org/10.1021/acsmaterialsau.3c00038
ACS Biomater Sci Eng. 2024 Jul 15.

Using Microfluidics to Align Matrix Architecture and Generate Chemokine Gradients Promotes Directional Branching in a Model of Epithelial Morphogenesis.

Jessanne Y Lichtenberg, Corinne E Leonard, Hazel R Sterling, Valentina Santos Agreda, Priscilla Y Hwang.

  The mechanical cue of fiber alignment plays a key role in the development of various tissues in the body. The ability to study the effect of these stimuli in vitro has been limited previously. Here, we present a microfluidic device capable of intrinsically generating aligned fibers using the microchannel geometry. The device also features tunable interstitial fluid flow and the ability to form a morphogen gradient. These aspects allow for the modeling of complex tissues and to differentiate cell response to different stimuli. To demonstrate the abilities of our device, we incorporated luminal epithelial cysts into our device and induced growth factor stimulation. We found the mechanical cue of fiber alignment to play a dominant role in cell elongation and the ability to form protrusions was dependent on cadherin-3. Together, this work serves as a springboard for future potential with these devices to answer questions in developmental biology and complex diseases such as cancers.

Keywords:  chemokine gradients; extracellular matrix; fiber alignment; mechanical cues; microenvironment; microfluidics

DOI:  https://doi.org/10.1021/acsbiomaterials.4c00245
bioRxiv. 2024 Jul 02. pii: 2024.06.27.601015. [Epub ahead of print]

Mechanical evolution of metastatic cancer cells in three-dimensional microenvironment.

Karlin Hilai, Daniil Grubich, Marcus Akrawi, Hui Zhu, Razanne Zaghloul, Chenjun Shi, Man Do, Dongxiao Zhu, Jitao Zhang.

  Cellular biomechanics plays critical roles in cancer metastasis and tumor progression. Existing studies on cancer cell biomechanics are mostly conducted in flat 2D conditions, where cells' behavior can differ considerably from those in 3D physiological environments. Despite great advances in developing 3D in vitro models, probing cellular elasticity in 3D conditions remains a major challenge for existing technologies. In this work, we utilize optical Brillouin microscopy to longitudinally acquire mechanical images of growing cancerous spheroids over the period of eight days. The dense mechanical mapping from Brillouin microscopy enables us to extract spatially resolved and temporally evolving mechanical features that were previously inaccessible. Using an established machine learning algorithm, we demonstrate that incorporating these extracted mechanical features significantly improves the classification accuracy of cancer cells, from 74% to 95%. Building on this finding, we have developed a deep learning pipeline capable of accurately differentiating cancerous spheroids from normal ones solely using Brillouin images, suggesting the mechanical features of cancer cells could potentially serve as a new biomarker in cancer classification and detection.

Keywords:  3D microenvironment; Brillouin microscopy; biomechanics; breast cancer; cellular spheroid; metastasis

DOI:  https://doi.org/10.1101/2024.06.27.601015
Methods Enzymol. 2024 ;pii: S0076-6879(24)00123-X. [Epub ahead of print]701 359-386

Free energy calculations for membrane morphological transformations and insights to physical biology and oncology.

Kshitiz Parihar, Seung-Hyun Ko, Ryan Bradley, Phillip Taylor, N Ramakrishnan, Tobias Baumgart, Wei Guo, Valerie M Weaver, Paul A Janmey, Ravi Radhakrishnan.

  In this chapter, we aim to bridge basic molecular and cellular principles surrounding membrane curvature generation with rewiring of cellular signals in cancer through multiscale models. We describe a general framework that integrates signaling with other cellular functions like trafficking, cell-cell and cell-matrix adhesion, and motility. The guiding question in our approach is: how does a physical change in cell membrane configuration caused by external stimuli (including those by the extracellular microenvironment) alter trafficking, signaling and subsequent cell fate? We answer this question by constructing a modeling framework based on stochastic spatial continuum models of cell membrane deformations. We apply this framework to explore the link between trafficking, signaling in the tumor microenvironment, and cell fate. At each stage, we aim to connect the results of our predictions with cellular experiments.

Keywords:  Curvature sensing; Dynamically triangulated Monte Carlo; Free energy methods; Membrane morphological transitions; Trafficking; Vesiculation

DOI:  https://doi.org/10.1016/bs.mie.2024.03.028
bioRxiv. 2024 Jul 13. pii: 2023.10.29.564655. [Epub ahead of print]

Biophysical modeling identifies an optimal hybrid amoeboid-mesenchymal phenotype for maximal T cell migration speeds.

Roberto Alonso-Matilla, Paolo P Provenzano, David J Odde.

Despite recent experimental progress in characterizing cell migration mechanics, our understanding of the mechanisms governing rapid cell movement remains limited. To effectively limit tumor growth, antitumoral T cells need to rapidly migrate to find and kill cancer cells. To investigate the upper limits of cell speed, we developed a new hybrid stochastic-mean field model of bleb-based cell motility. We first examined the potential for adhesion-free bleb-based migration and show that cells migrate inefficiently in the absence of adhesion-based forces, i.e., cell swimming. While no cortical contractility oscillations are needed for cells to swim in viscoelastic media, high-to-low cortical contractility oscillations are necessary for cell swimming in viscous media. This involves a high cortical contractility phase with multiple bleb nucleation events, followed by an intracellular pressure buildup recovery phase at low cortical tensions, resulting in modest net cell motion. However, our model suggests that cells can employ a hybrid bleb- and adhesion-based migration mechanism for rapid cell motility and identifies conditions for optimality. The model provides a momentum-conserving mechanism underlying rapid single-cell migration and identifies factors as design criteria for engineering T cell therapies to improve movement in mechanically complex environments.

DOI: https://doi.org/10.1101/2023.10.29.564655
Nat Commun. 2024 Jul 13. 15(1): 5891

Engineering programmable material-to-cell pathways via synthetic notch receptors to spatially control differentiation in multicellular constructs.

Mher Garibyan, Tyler Hoffman, Thijs Makaske, Stephanie K Do, Yifan Wu, Brian A Williams, Alexander R March, Nathan Cho, Nicolas Pedroncelli, Ricardo Espinosa Lima, Jennifer Soto, Brooke Jackson, Jeffrey W Santoso, Ali Khademhosseini, Matt Thomson, Song Li, Megan L McCain, Leonardo Morsut.

Synthetic Notch (synNotch) receptors are genetically encoded, modular synthetic receptors that enable mammalian cells to detect environmental signals and respond by activating user-prescribed transcriptional programs. Although some materials have been modified to present synNotch ligands with coarse spatial control, applications in tissue engineering generally require extracellular matrix (ECM)-derived scaffolds and/or finer spatial positioning of multiple ligands. Thus, we develop here a suite of materials that activate synNotch receptors for generalizable engineering of material-to-cell signaling. We genetically and chemically fuse functional synNotch ligands to ECM proteins and ECM-derived materials. We also generate tissues with microscale precision over four distinct reporter phenotypes by culturing cells with two orthogonal synNotch programs on surfaces microcontact-printed with two synNotch ligands. Finally, we showcase applications in tissue engineering by co-transdifferentiating fibroblasts into skeletal muscle or endothelial cell precursors in user-defined micropatterns. These technologies provide avenues for spatially controlling cellular phenotypes in mammalian tissues.

DOI: https://doi.org/10.1038/s41467-024-50126-1
Proc Natl Acad Sci U S A. 2024 Jul 23. 121(30): e2410708121

A geometrical theory of gliding motility based on cell shape and surface flow.

Leon Lettermann, Falko Ziebert, Ulrich S Schwarz.

  Gliding motility proceeds with little changes in cell shape and often results from actively driven surface flows of adhesins binding to the extracellular environment. It allows for fast movement over surfaces or through tissue, especially for the eukaryotic parasites from the phylum apicomplexa, which includes the causative agents of the widespread diseases malaria and toxoplasmosis. We have developed a fully three-dimensional active particle theory which connects the self-organized, actively driven surface flow over a fixed cell shape to the resulting global motility patterns. Our analytical solutions and numerical simulations show that straight motion without rotation is unstable for simple shapes and that straight cell shapes tend to lead to pure rotations. This suggests that the curved shapes of Plasmodium sporozoites and Toxoplasma tachyzoites are evolutionary adaptations to avoid rotations without translation. Gliding motility is also used by certain myxo- or flavobacteria, which predominantly move on flat external surfaces and with higher control of cell surface flow through internal tracks. We extend our theory for these cases. We again find a competition between rotation and translation and predict the effect of internal track geometry on overall forward speed. While specific mechanisms might vary across species, in general, our geometrical theory predicts and explains the rotational, circular, and helical trajectories which are commonly observed for microgliders. Our theory could also be used to design synthetic microgliders.

Keywords:  bifurcations; cell motility; microgliders; motility patterns; stability analysis

DOI:  https://doi.org/10.1073/pnas.2410708121
bioRxiv. 2024 Jul 10. pii: 2024.07.06.602364. [Epub ahead of print]

Fully synthetic hydrogels promote robust crypt formation in intestinal organoids.

Ella A Hushka, Michael R Blatchley, Laura J Macdougall, F Max Yavitt, Bruce E Kirkpatrick, Kaustav Bera, Peter J Dempsey, Kristi S Anseth.

Initial landmark studies in the design of synthetic hydrogels for intestinal organoid culture identified precise matrix requirements for differentiation, namely decompression of matrix-imposed forces and supplementation of laminin. But beyond stating the necessity of laminin, organoid-laminin interactions have gone largely unstudied, as this ubiquitous requirement of exogenous laminin hinders investigation. In this work, we exploit a fast stress relaxing, boronate ester based synthetic hydrogel for the culture of intestinal organoids, and fortuitously discover that unlike all other synthetic hydrogels to date, laminin does not need to be supplemented for crypt formation. This highly defined material provides a unique opportunity to investigate laminin-organoid interactions and how it influences crypt evolution and organoid function. Via fluorescent labeling of non-canonical amino acids, we further show that adaptable boronate ester bonds increase deposition of nascent proteins, including laminin. Collectively, these results advance the understanding of how mechanical and matricellular signaling influence intestinal organoid development.

DOI: https://doi.org/10.1101/2024.07.06.602364
bioRxiv. 2024 Jul 02. pii: 2024.06.28.601261. [Epub ahead of print]

Polyploidy of MDA-MB-231 cells drives increased extravasation with enhanced cell-matrix adhesion.

Satomi Hirose, Tatsuya Osaki, Roger D Kamm.

Metastasis, the leading cause of cancer-related deaths, involves a complex cascade of events, including extravasation. Despite extensive research into metastasis, the mechanisms underlying extravasation remain unclear. Molecular targeted therapies have advanced cancer treatment, yet their efficacy is limited, prompting exploration into novel therapeutic targets. Here, we showed the association of polyploidy in MDA-MB-231 breast cancer cells and their extravasation, using microfluidic systems to reproduce the in vivo microvascular environment. We observed enhanced extravasation in polyploid cells alongside upregulated expression of genes involved in cell-substrate adhesion and cell mechanical dynamics. These findings offer insights into the relationship between polyploidy and extravasation, highlighting potential targets for cancer therapy.

DOI: https://doi.org/10.1101/2024.06.28.601261