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1.
Life Sci Alliance ; 7(9)2024 Sep.
Article de Anglais | MEDLINE | ID: mdl-39025524

RÉSUMÉ

Epithelia consist of proliferating and differentiating cells that often display patterned arrangements. However, the mechanism regulating these spatial arrangements remains unclear. Here, we show that cell-cell adhesion dictates multicellular patterning in stratified epithelia. When cultured keratinocytes, a type of epithelial cell in the skin, are subjected to starvation, they spontaneously develop a pattern characterized by areas of high and low cell density. Pharmacological and knockout experiments show that adherens junctions are essential for patterning, whereas the mathematical model that only considers local cell-cell adhesion as a source of attractive interactions can form regions with high/low cell density. This phenomenon, called cell-cell adhesion-induced patterning (CAIP), influences cell differentiation and proliferation through Yes-associated protein modulation. Starvation, which induces CAIP, enhances the stratification of the epithelia. These findings highlight the intrinsic self-organizing property of epithelial cells.


Sujet(s)
Jonctions adhérentes , Adhérence cellulaire , Différenciation cellulaire , Prolifération cellulaire , Cellules épithéliales , Kératinocytes , Adhérence cellulaire/physiologie , Kératinocytes/métabolisme , Kératinocytes/cytologie , Différenciation cellulaire/génétique , Humains , Cellules épithéliales/métabolisme , Cellules épithéliales/cytologie , Jonctions adhérentes/métabolisme , Animaux , Épithélium/métabolisme , Souris , Cellules cultivées
2.
Proc Natl Acad Sci U S A ; 121(31): e2320372121, 2024 Jul 30.
Article de Anglais | MEDLINE | ID: mdl-39042691

RÉSUMÉ

Cells exist in different phenotypes and can transition between them. A phenotype may be characterized by many different aspects. Here, we focus on the example of whether the cell is adhered or suspended and choose particular parameters related to the structure and mechanics of the actin cortex. The cortex is essential to cell mechanics, morphology, and function, such as for adhesion, migration, and division of animal cells. To predict and control cellular functions and prevent malfunctioning, it is necessary to understand the actin cortex. The structure of the cortex governs cell mechanics; however, the relationship between the architecture and mechanics of the cortex is not yet well enough understood to be able to predict one from the other. Therefore, we quantitatively measured structural and mechanical cortex parameters, including cortical thickness, cortex mesh size, actin bundling, and cortex stiffness. These measurements required developing a combination of measurement techniques in scanning electron, expansion, confocal, and atomic force microscopy. We found that the structure and mechanics of the cortex of cells in interphase are different depending on whether the cell is suspended or adhered. We deduced general correlations between structural and mechanical properties and show how these findings can be explained within the framework of semiflexible polymer network theory. We tested the model predictions by perturbing the properties of the actin within the cortex using compounds. Our work provides an important step toward predictions of cell mechanics from cortical structures and suggests how cortex remodeling between different phenotypes impacts the mechanical properties of cells.


Sujet(s)
Actines , Adhérence cellulaire , Adhérence cellulaire/physiologie , Actines/métabolisme , Animaux , Microscopie à force atomique/méthodes , Phénomènes biomécaniques , Modèles biologiques
3.
Sensors (Basel) ; 24(11)2024 May 24.
Article de Anglais | MEDLINE | ID: mdl-38894171

RÉSUMÉ

Adherent cells perceive mechanical feedback from the underlying matrix and convert it into biochemical signals through a process known as mechanotransduction. The response to changes in the microenvironment relies on the cell's mechanical properties, including elasticity, which was recently identified as a biomarker for various diseases. Here, we propose the design, development, and characterization of a new system for the measurement of adherent cells' strain drop, a parameter correlated with cells' elasticity. To consider the interplay between adherent cells and the host extracellular matrix, cell stretching was combined with adhesion on substrates with different stiffnesses. The technique is based on the linear stretching of silicone chambers, high-speed image acquisition, and feedback for image centering. The system was characterized in terms of the strain homogeneity, impact of collagen coating, centering capability, and sensitivity. Subsequently, it was employed to measure the strain drop of two osteosarcoma cell lines, low-aggressive osteoblast-like SaOS-2 and high-aggressive 143B, cultured on two different substrates to recall the stiffness of the bone and lung extracellular matrices. Results demonstrated good substrate homogeneity, a negligible effect of the collagen coating, and an accurate image centering. Finally, the experimental results showed an average strain drop that was lower in the 143B cells in comparison with the SaOS-2 cells in all the tested conditions.


Sujet(s)
Ostéosarcome , Ostéosarcome/anatomopathologie , Humains , Lignée cellulaire tumorale , Matrice extracellulaire/métabolisme , Mécanotransduction cellulaire/physiologie , Adhérence cellulaire/physiologie , Élasticité , Contrainte mécanique , Tumeurs osseuses/anatomopathologie , Collagène/composition chimique , Collagène/métabolisme , Ostéoblastes/cytologie , Ostéoblastes/physiologie
4.
PLoS Comput Biol ; 20(6): e1012112, 2024 Jun.
Article de Anglais | MEDLINE | ID: mdl-38861575

RÉSUMÉ

Cell sedimentation in 3D hydrogel cultures refers to the vertical migration of cells towards the bottom of the space. Understanding this poorly examined phenomenon may allow us to design better protocols to prevent it, as well as provide insights into the mechanobiology of cancer development. We conducted a multiscale experimental and mathematical examination of 3D cancer growth in triple negative breast cancer cells. Migration was examined in the presence and absence of Paclitaxel, in high and low adhesion environments and in the presence of fibroblasts. The observed behaviour was modeled by hypothesizing active migration due to self-generated chemotactic gradients. Our results did not reject this hypothesis, whereby migration was likely to be regulated by the MAPK and TGF-ß pathways. The mathematical model enabled us to describe the experimental data in absence (normalized error<40%) and presence of Paclitaxel (normalized error<10%), suggesting inhibition of random motion and advection in the latter case. Inhibition of sedimentation in low adhesion and co-culture experiments further supported the conclusion that cells actively migrated downwards due to the presence of signals produced by cells already attached to the adhesive glass surface.


Sujet(s)
Adhérence cellulaire , Mouvement cellulaire , Paclitaxel , Humains , Adhérence cellulaire/physiologie , Mouvement cellulaire/physiologie , Paclitaxel/pharmacologie , Lignée cellulaire tumorale , Modèles biologiques , Techniques de cultures cellulaires tridimensionnelles/méthodes , Tumeurs du sein triple-négatives/anatomopathologie , Biologie informatique , Fibroblastes/physiologie , Chimiotaxie/physiologie
5.
Cell Immunol ; 401-402: 104843, 2024.
Article de Anglais | MEDLINE | ID: mdl-38905771

RÉSUMÉ

Monocyte migration is an important process in inflammation and atherogenesis. Identification of the key signalling pathways that regulate monocyte migration can provide prospective targets for prophylactic treatments in inflammatory diseases. Previous research showed that the focal adhesion kinase Pyk2, Src kinase and MAP kinases play an important role in MCP-1-induced monocyte migration. In this study, we demonstrate that MCP-1 induces iPLA2 activity, which is regulated by PKCß and affects downstream activation of Rac1 and Pyk2. Rac1 interacts directly with iPLA2 and Pyk2, and plays a crucial role in MCP-1-mediated monocyte migration by modulating downstream Pyk2 and p38 MAPK activation. Furthermore, Rac1 is necessary for cell spreading and F-actin polymerization during monocyte adhesion to fibronectin. Finally, we provide evidence that Rac1 controls the secretion of inflammatory mediator vimentin from MCP-1-stimulated monocytes. Altogether, this study demonstrates that the PKCß/iPLA2/Rac1/Pyk2/p38 MAPK signalling cascade is essential for MCP-1-induced monocyte adhesion and migration.


Sujet(s)
Adhérence cellulaire , Mouvement cellulaire , Chimiokine CCL2 , Focal adhesion kinase 2 , Monocytes , Transduction du signal , p38 Mitogen-Activated Protein Kinases , Protéine G rac1 , Humains , Monocytes/métabolisme , Monocytes/immunologie , Chimiokine CCL2/métabolisme , Adhérence cellulaire/physiologie , Protéine G rac1/métabolisme , Focal adhesion kinase 2/métabolisme , p38 Mitogen-Activated Protein Kinases/métabolisme , Protein kinase C beta/métabolisme , Actines/métabolisme
6.
Mol Biol Cell ; 35(8): ar110, 2024 Aug 01.
Article de Anglais | MEDLINE | ID: mdl-38922850

RÉSUMÉ

Contractile myosin and cell adhesion work together to induce tissue shape changes, but how they are patterned to achieve diverse morphogenetic outcomes remains unclear. Epithelial folding occurs via apical constriction, mediated by apical contractile myosin engaged with adherens junctions, as in Drosophila ventral furrow formation. While it has been shown that a multicellular gradient of myosin contractility determines folding shape, the impact of multicellular patterning of adherens junction levels on tissue folding is unknown. We identified a novel Drosophila gene moat essential for differential apical constriction and folding behaviors across the ventral epithelium which contains both folding ventral furrow and nonfolding ectodermal anterior midgut (ectoAMG). We show that Moat functions to downregulate polarity-dependent adherens junctions through inhibiting cortical clustering of Bazooka/Par3 proteins. Such downregulation of polarity-dependent junctions is critical for establishing a myosin-dependent pattern of adherens junctions, which in turn mediates differential apical constriction in the ventral epithelium. In moat mutants, abnormally high levels of polarity-dependent junctions promote ectopic apical constriction in cells with low-level contractile myosin, resulting in expansion of infolding from ventral furrow to ectoAMG, and flattening of ventral furrow constriction gradient. Our results demonstrate that tissue-scale distribution of adhesion levels patterns apical constriction and establishes morphogenetic boundaries.


Sujet(s)
Jonctions adhérentes , Polarité de la cellule , Protéines de Drosophila , Drosophila melanogaster , Animaux , Jonctions adhérentes/métabolisme , Protéines de Drosophila/métabolisme , Protéines de Drosophila/génétique , Drosophila melanogaster/métabolisme , Polarité de la cellule/physiologie , Épithélium/métabolisme , Myosines/métabolisme , Cellules épithéliales/métabolisme , Adhérence cellulaire/physiologie , Morphogenèse , Protéines et peptides de signalisation intracellulaire
7.
J Biomed Opt ; 29(Suppl 2): S22708, 2024 Jun.
Article de Anglais | MEDLINE | ID: mdl-38872791

RÉSUMÉ

Significance: The ability to observe and monitor cell density and morphology has been imperative for assessing the health of a cell culture and for producing high quality, high yield cell cultures for decades. Microcarrier-based cultures, used for large-scale cellular expansion processes, are not compatible with traditional visualization-based methods, such as widefield microscopy, due to their thickness and material composition. Aim: Here, we assess the optical imaging compatibilities of commercial polystyrene microcarriers versus custom-fabricated gelatin methacryloyl (gelMA) microcarriers for non-destructive and non-invasive visualization of the entire microcarrier surface, direct cell enumeration, and sub-cellular visualization of mesenchymal stem/stromal cells. Approach: Mie scattering and wavefront error simulations of the polystyrene and gelMA microcarriers were performed to assess the potential for elastic scattering-based imaging of adherent cells. A Zeiss Z.1 light-sheet microscope was adapted to perform light-sheet tomography using label-free elastic scattering contrast from planar side illumination to achieve optical sectioning and permit non-invasive and non-destructive, in toto, three-dimensional, high-resolution visualization of cells cultured on microcarriers. Results: The polystyrene microcarrier prevents visualization of cells on the distal half of the microcarrier using either fluorescence or elastic scattering contrast, whereas the gelMA microcarrier allows for high fidelity visualization of cell morphology and quantification of cell density using light-sheet fluorescence microscopy and tomography. Conclusions: The combination of optical-quality gelMA microcarriers and label-free light-sheet tomography will facilitate enhanced control of bioreactor-microcarrier cell culture processes.


Sujet(s)
Adhérence cellulaire , Hydrogels , Cellules souches mésenchymateuses , Polystyrènes , Polystyrènes/composition chimique , Cellules souches mésenchymateuses/cytologie , Hydrogels/composition chimique , Adhérence cellulaire/physiologie , Imagerie optique/méthodes , Imagerie optique/instrumentation , Humains , Gélatine/composition chimique , Techniques de culture cellulaire/méthodes , Techniques de culture cellulaire/instrumentation , Cellules cultivées , Animaux
8.
Mol Immunol ; 171: 12-21, 2024 Jul.
Article de Anglais | MEDLINE | ID: mdl-38735126

RÉSUMÉ

Macrophages are critical in mediating immune and inflammatory responses, while monocyte-to-macrophage differentiation is one of the main macrophage resources that involves various matrix proteins. Matrix remodeling associated 7 (MXRA7) was recently discovered to affect a variety of physiological and pathological processes related to matrix biology. In the present study, we investigated the role of MXRA7 in monocyte-to-macrophage differentiation in vitro. We found that knockdown of MXRA7 inhibited the proliferation of THP-1 human monocytic cells. Knockdown of MXRA7 increased the adhesion ability of THP-1 cells through upregulation the expression of adhesion molecules VCAM-1 and ICAM1. Knockdown of MXRA7 alone could promoted the differentiation of THP-1 cells to macrophages. Furthermore, the MXRA7-knockdown THP-1 cells produced a more significant upregulation pattern with M1-type cytokines (TNF-α, IL-1ß and IL-6) than with those M2-type molecules (TGF-ß1 and IL-1RA) upon PMA stimulation, indicating that knockdown of MXRA7 facilitated THP-1 cells differentiation toward M1 macrophages. RNA sequencing analysis revealed the potential biological roles of MXRA7 in cell adhesion, macrophage and monocyte differentiation. Moreover, MXRA7 knockdown promoted the expression of NF-κB p52/p100, while PMA stimulation could increase the expression of NF-κB p52/p100 and activating MAPK signaling pathways in MXRA7 knockdown cells. In conclusion, MXRA7 affected the differentiation of THP-1 cells toward macrophages possibly through NF-κB signaling pathways.


Sujet(s)
Différenciation cellulaire , Macrophages , Monocytes , Humains , Adhérence cellulaire/physiologie , Différenciation cellulaire/immunologie , Différenciation cellulaire/génétique , Prolifération cellulaire , Cytokines/métabolisme , Techniques de knock-down de gènes , Molécule-1 d'adhérence intercellulaire/métabolisme , Molécule-1 d'adhérence intercellulaire/génétique , Macrophages/métabolisme , Macrophages/immunologie , Monocytes/métabolisme , Facteur de transcription NF-kappa B/métabolisme , Transduction du signal , Cellules THP-1 , Molécule-1 d'adhérence des cellules vasculaires/métabolisme , Molécule-1 d'adhérence des cellules vasculaires/génétique
9.
Proc Natl Acad Sci U S A ; 121(22): e2318248121, 2024 May 28.
Article de Anglais | MEDLINE | ID: mdl-38787878

RÉSUMÉ

For eukaryotic cells to heal wounds, respond to immune signals, or metastasize, they must migrate, often by adhering to extracellular matrix (ECM). Cells may also deposit ECM components, leaving behind a footprint that influences their crawling. Recent experiments showed that some epithelial cell lines on micropatterned adhesive stripes move persistently in regions they have previously crawled over, where footprints have been formed, but barely advance into unexplored regions, creating an oscillatory migration of increasing amplitude. Here, we explore through mathematical modeling how footprint deposition and cell responses to footprint combine to allow cells to develop oscillation and other complex migratory motions. We simulate cell crawling with a phase field model coupled to a biochemical model of cell polarity, assuming local contact with the deposited footprint activates Rac1, a protein that establishes the cell's front. Depending on footprint deposition rate and response to the footprint, cells on micropatterned lines can display many types of motility, including confined, oscillatory, and persistent motion. On two-dimensional (2D) substrates, we predict a transition between cells undergoing circular motion and cells developing an exploratory phenotype. Small quantitative changes in a cell's interaction with its footprint can completely alter exploration, allowing cells to tightly regulate their motion, leading to different motility phenotypes (confined vs. exploratory) in different cells when deposition or sensing is variable from cell to cell. Consistent with our computational predictions, we find in earlier experimental data evidence of cells undergoing both circular and exploratory motion.


Sujet(s)
Mouvement cellulaire , Matrice extracellulaire , Mouvement cellulaire/physiologie , Matrice extracellulaire/métabolisme , Matrice extracellulaire/physiologie , Protéine G rac1/métabolisme , Humains , Polarité de la cellule/physiologie , Modèles biologiques , Animaux , Adhérence cellulaire/physiologie , Cellules épithéliales/métabolisme , Cellules épithéliales/cytologie , Cellules épithéliales/physiologie
10.
Mol Biol Cell ; 35(7): ar102, 2024 Jul 01.
Article de Anglais | MEDLINE | ID: mdl-38809584

RÉSUMÉ

Interferon Regulatory Factor 6 (IRF6) is a transcription factor essential for keratinocyte cell-cell adhesions. Previously, we found that recycling of E-cadherin was defective in the absence of IRF6, yet total E-cadherin levels were not altered, suggesting a previously unknown, nontranscriptional function for IRF6. IRF6 protein contains a DNA binding domain (DBD) and a protein binding domain (PBD). The transcriptional function of IRF6 depends on its DBD and PBD, however, whether the PBD is necessary for the interaction with cytoplasmic proteins has yet to be demonstrated. Here, we show that an intact PBD is required for recruitment of cell-cell adhesion proteins at the plasma membrane, including the recycling of E-cadherin. Colocalizations and coimmunoprecipitations reveal that IRF6 forms a complex in recycling endosomes with Rab11, Myosin Vb, and E-cadherin, and that the PBD is required for this interaction. These data indicate that IRF6 is a novel effector of the endosomal recycling of E-cadherin and demonstrate a non-transcriptional function for IRF6 in regulating cell-cell adhesions.


Sujet(s)
Cadhérines , Adhérence cellulaire , Endosomes , Facteurs de régulation d'interféron , Animaux , Humains , Souris , Cadhérines/métabolisme , Adhérence cellulaire/physiologie , Membrane cellulaire/métabolisme , Endosomes/métabolisme , Facteurs de régulation d'interféron/métabolisme , Facteurs de régulation d'interféron/génétique , Kératinocytes/métabolisme , Liaison aux protéines , Domaines protéiques , Transport des protéines , Protéines G rab/métabolisme
11.
J Vis Exp ; (207)2024 May 03.
Article de Anglais | MEDLINE | ID: mdl-38767378

RÉSUMÉ

Ultrashort self-assembling peptides (SAPs) can spontaneously form nanofibers that resemble the extracellular matrix. These fibers allow the formation of hydrogels that are biocompatible, biodegradable, and non-immunogenic. We have previously proven that SAPs, when biofunctionalized with protein-derived motifs, can mimic the extracellular matrix characteristics that support colorectal organoid formation. These biofunctional peptide hydrogels retain the original parent peptide's mechanical properties, tunability, and printability while incorporating cues that allow cell-matrix interactions to increase cell adhesion. This paper presents the protocols needed to evaluate and characterize the effects of various biofunctional peptide hydrogels on cell adhesion and lumen formation using an adenocarcinoma cancer cell line able to form colorectal cancer organoids cost-effectively. These protocols will help evaluate biofunctional peptide hydrogel effects on cell adhesion and luminal formation using immunostaining and fluorescence image analysis. The cell line used in this study has been previously utilized for generating organoids in animal-derived matrices.


Sujet(s)
Tumeurs colorectales , Hydrogels , Organoïdes , Peptides , Organoïdes/cytologie , Humains , Tumeurs colorectales/anatomopathologie , Lignée cellulaire tumorale , Hydrogels/composition chimique , Peptides/composition chimique , Nanofibres/composition chimique , Adénocarcinome/anatomopathologie , Matrice extracellulaire/composition chimique , Adhérence cellulaire/physiologie
12.
Phys Rev Lett ; 132(18): 188402, 2024 May 03.
Article de Anglais | MEDLINE | ID: mdl-38759206

RÉSUMÉ

Cell adhesion receptors are transmembrane proteins that bind cells to their environment. These proteins typically cluster into disk-shaped or linear structures. Here, we show that such clustering patterns spontaneously emerge when the receptor senses the membrane deformation gradient, for example, by reaching a lower-energy conformation when the membrane is tilted relative to the underlying binding substrate. Increasing the strength of the membrane gradient-sensing mechanism first yields isolated disk-shaped clusters and then long linear structures. Our theory is coherent with experimental estimates of the parameters, suggesting that a tilt-induced clustering mechanism is relevant in the context of cell adhesion.


Sujet(s)
Membrane cellulaire , Membrane cellulaire/métabolisme , Modèles biologiques , Adhérence cellulaire/physiologie , , Complexe glycoprotéique GPIb-IX plaquettaire
13.
Invest Ophthalmol Vis Sci ; 65(5): 4, 2024 May 01.
Article de Anglais | MEDLINE | ID: mdl-38691089

RÉSUMÉ

Purpose: To investigate the adhesion of Acanthamoeba to scleral contact lens (ScCL) surface according to lens shape. Methods: Two strains of A. polyphaga (CDC:V062 and ATCC 30461) and one clinical Acanthamoeba isolate, were inoculated onto five contact lens (CL): one first-generation silicone hydrogel (SHCL; lotrafilcon B; adhesion control) containing plasma surface treatment; two ScCL (fluorosilicone acrylate) one containing surface treatment composed of plasma and the other containing plasma with Hydra-PEG, and two CL designed with a flat shape having the same material and surface treatments of the ScCL. Trophozoites that adhered to the lens's surfaces were counted by inverted optical light microscopy. Possible alterations of the lens surface that could predispose amoeba adhesion and Acanthamoeba attached to these lens surfaces were evaluated by scanning electron microscopy (SEM). Results: All strains revealed greater adhesion to the ScCL when compared with the flat lenses (P < 0.001). The clinical isolate and the ATCC 30461 had a higher adhesion (P < 0.001) when compared with the CDC:V062. A rough texture was observed on the surface of the lenses that have been examined by SEM. Also, SEM revealed that the isolates had a rounded appearance on the surface of the ScCL in contrast with an elongated appearance on the surface of the silicone hydrogel. Conclusions: The findings revealed that the curved shape of the ScCL favors amoeba adhesion.


Sujet(s)
Acanthamoeba , Microscopie électronique à balayage , Acanthamoeba/physiologie , Acanthamoeba/ultrastructure , Sclère , Humains , Lentilles de contact hydrophiles/parasitologie , Adhérence cellulaire/physiologie , Lentilles de contact/parasitologie , Trophozoïtes/ultrastructure , Trophozoïtes/physiologie , Hydrogels , Animaux
14.
J R Soc Interface ; 21(214): 20240022, 2024 May.
Article de Anglais | MEDLINE | ID: mdl-38715321

RÉSUMÉ

Using a three-dimensional model of cell monolayers, we study the spatial organization of active stress chains as the monolayer transitions from a solid to a liquid state. The critical exponents that characterize this transition map the isotropic stress percolation onto the two-dimensional random percolation universality class, suggesting short-range stress correlations near this transition. This mapping is achieved via two distinct, independent pathways: (i) cell-cell adhesion and (ii) active traction forces. We unify our findings by linking the nature of this transition to high-stress fluctuations, distinctly linked to each pathway. The results elevate the importance of the transmission of mechanical information in dense active matter and provide a new context for understanding the non-equilibrium statistical physics of phase transition in active systems.


Sujet(s)
Adhérence cellulaire , Modèles biologiques , Adhérence cellulaire/physiologie , Contrainte mécanique , Transition de phase
15.
J R Soc Interface ; 21(214): 20240105, 2024 May.
Article de Anglais | MEDLINE | ID: mdl-38774959

RÉSUMÉ

During mesenchymal migration, F-actin protrusion at the leading edge and actomyosin contraction determine the retrograde flow of F-actin within the lamella. The coupling of this flow to integrin-based adhesions determines the force transmitted to the extracellular matrix and the net motion of the cell. In tissues, motion may also arise from convection, driven by gradients in tissue-scale surface tensions and pressures. However, how migration coordinates with convection to determine the net motion of cellular ensembles is unclear. To explore this, we study the spreading of cell aggregates on adhesive micropatterns on compliant substrates. During spreading, a cell monolayer expands from the aggregate towards the adhesive boundary. However, cells are unable to stabilize the protrusion beyond the adhesive boundary, resulting in retraction of the protrusion and detachment of cells from the matrix. Subsequently, the cells move upwards and rearwards, yielding a bulk convective flow towards the centre of the aggregate. The process is cyclic, yielding a steady-state balance between outward (protrusive) migration along the surface, and 'retrograde' (contractile) flows above the surface. Modelling the cell aggregates as confined active droplets, we demonstrate that the interplay between surface tension-driven flows within the aggregate, radially outward monolayer flow and conservation of mass leads to an internal circulation.


Sujet(s)
Adhérence cellulaire , Mouvement cellulaire , Modèles biologiques , Mouvement cellulaire/physiologie , Adhérence cellulaire/physiologie , Agrégation cellulaire/physiologie , Animaux , Humains , Actines/métabolisme
16.
J Phys Condens Matter ; 36(29)2024 Apr 18.
Article de Anglais | MEDLINE | ID: mdl-38574682

RÉSUMÉ

Cell-matrix adhesions connect the cytoskeleton to the extracellular environment and are essential for maintaining the integrity of tissue and whole organisms. Remarkably, cell adhesions can adapt their size and composition to an applied force such that their size and strength increases proportionally to the load. Mathematical models for the clutch-like force transmission at adhesions are frequently based on the assumption that mechanical load is applied tangentially to the adhesion plane. Recently, we suggested a molecular mechanism that can explain adhesion growth under load for planar cell adhesions. The mechanism is based on conformation changes of adhesion molecules that are dynamically exchanged with a reservoir. Tangential loading drives the occupation of some states out of equilibrium, which for thermodynamic reasons, leads to the association of further molecules with the cluster, which we refer to as self-stabilization. Here, we generalize this model to forces that pull at an oblique angle to the plane supporting the cell, and examine if this idealized model also predicts self-stabilization. We also allow for a variable distance between the parallel planes representing cytoskeletal F-actin and transmembrane integrins. Simulation results demonstrate that the binding mechanism and the geometry of the cluster have a strong influence on the response of adhesion clusters to force. For oblique angles smaller than about 40∘, we observe a growth of the adhesion site under force. However this self-stabilization is reduced as the angle between the force and substrate plane increases, with vanishing self-stabilization for normal pulling. Overall, these results highlight the fundamental difference between the assumption of pulling and shearing forces in commonly used models of cell adhesion.


Sujet(s)
Matrice extracellulaire , Contacts focaux , Contacts focaux/métabolisme , Matrice extracellulaire/métabolisme , Adhérence cellulaire/physiologie , Actines , Intégrines/métabolisme
17.
Nat Comput Sci ; 4(4): 299-309, 2024 Apr.
Article de Anglais | MEDLINE | ID: mdl-38594592

RÉSUMÉ

The three-dimensional (3D) organization of cells determines tissue function and integrity, and changes markedly in development and disease. Cell-based simulations have long been used to define the underlying mechanical principles. However, high computational costs have so far limited simulations to either simplified cell geometries or small tissue patches. Here, we present SimuCell3D, an efficient open-source program to simulate large tissues in three dimensions with subcellular resolution, growth, proliferation, extracellular matrix, fluid cavities, nuclei and non-uniform mechanical properties, as found in polarized epithelia. Spheroids, vesicles, sheets, tubes and other tissue geometries can readily be imported from microscopy images and simulated to infer biomechanical parameters. Doing so, we show that 3D cell shapes in layered and pseudostratified epithelia are largely governed by a competition between surface tension and intercellular adhesion. SimuCell3D enables the large-scale in silico study of 3D tissue organization in development and disease at a great level of detail.


Sujet(s)
Polarité de la cellule , Simulation numérique , Modèles biologiques , Phénomènes biomécaniques/physiologie , Adhérence cellulaire/physiologie , Polarité de la cellule/physiologie , Forme de la cellule/physiologie , Cellules épithéliales/physiologie , Cellules épithéliales/cytologie , Matrice extracellulaire/physiologie , Matrice extracellulaire/composition chimique , Imagerie tridimensionnelle/méthodes , Logiciel
19.
Mol Biol Cell ; 35(5): ar65, 2024 May 01.
Article de Anglais | MEDLINE | ID: mdl-38507238

RÉSUMÉ

α-catenin (α-cat) displays force-dependent unfolding and binding to actin filaments through direct and indirect means, but features of adherens junction structure and function most vulnerable to loss of these allosteric mechanisms have not been directly compared. By reconstituting an α-cat F-actin-binding domain unfolding mutant known to exhibit enhanced binding to actin (α-cat-H0-FABD+) into α-cat knockout Madin Darby Canine Kidney (MDCK) cells, we show that partial loss of the α-cat catch bond mechanism (via an altered H0 α-helix) leads to stronger epithelial sheet integrity with greater colocalization between the α-cat-H0-FABD+ mutant and actin. α-cat-H0-FABD+ -expressing cells are less efficient at closing scratch-wounds, suggesting reduced capacity for more dynamic cell-cell coordination. Evidence that α-cat-H0-FABD+ is equally accessible to the conformationally sensitive α18 antibody epitope as WT α-cat and shows similar vinculin recruitment suggests this mutant engages lower tension cortical actin networks, as its M-domain is not persistently open. Conversely, α-cat-M-domain salt-bridge mutants with persistent recruitment of vinculin and phosphorylated myosin light chain show only intermediate monolayer adhesive strengths, but display less directionally coordinated and thereby slower migration speeds during wound-repair. These data show α-cat M- and FABD-unfolding mutants differentially impact cell-cell cohesion and migration properties, and suggest signals favoring α-cat-cortical actin interaction without persistent M-domain opening may improve epithelial monolayer strength through enhanced coupling to lower tension actin networks.


Sujet(s)
Cytosquelette d'actine , Actines , Mouvement cellulaire , Cellules épithéliales , alpha-Caténine , Chiens , Animaux , alpha-Caténine/métabolisme , alpha-Caténine/génétique , Cellules rénales canines Madin-Darby , Actines/métabolisme , Cellules épithéliales/métabolisme , Cytosquelette d'actine/métabolisme , Liaison aux protéines , Domaines protéiques , Mutation , Jonctions adhérentes/métabolisme , Dépliement des protéines , Adhérence cellulaire/physiologie , Vinculine/métabolisme
20.
Endocrinology ; 165(5)2024 Mar 29.
Article de Anglais | MEDLINE | ID: mdl-38518755

RÉSUMÉ

Seminal extracellular vesicles (EVs) contain different subgroups that have diverse effects on sperm function. However, the effect of seminal EVs-especially their subgroups-on endometrial receptivity is largely unknown. Here, we found that seminal EVs could be divided into high-density EVs (EV-H), medium density EVs, and low-density EVs after purification using iodixanol. We demonstrated that EV-H could promote the expression and secretion of leukemia inhibitor factor (LIF) in human endometrial cells. In EV-H-treated endometrial cells, we identified 1274 differentially expressed genes (DEGs). DEGs were enriched in cell adhesion and AKT and STAT3 pathways. Therefore, we illustrated that EV-H enhanced the adhesion of human choriocarcinoma JAr cell spheroids to endometrial cells through the LIF-STAT3 pathway. Collectively, our findings indicated that seminal EV-H could regulate endometrial receptivity through the LIF pathway, which could provide novel insights into male fertility.


Sujet(s)
Implantation embryonnaire , Vésicules extracellulaires , Femelle , Humains , Mâle , Grossesse , Adhérence cellulaire/physiologie , Implantation embryonnaire/physiologie , Endomètre/métabolisme , Vésicules extracellulaires/métabolisme , Facteur inhibiteur de la leucémie/métabolisme , Sperme/métabolisme
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