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- Minh-Uyen Dao Thi, Candice Trocmé, Marie-Paule Montmasson, Eric Fanchon, Bertrand Toussaint & Philippe Tracqui (forthcoming). Investigating Metalloproteinases MMP-2 and MMP-9 Mechanosensitivity to Feedback Loops Involved in the Regulation of In Vitro Angiogenesis by Endogenous Mechanical Stresses. Acta Biotheoretica.Abstract Angiogenesis is a complex morphogenetic process regulated by growth factors, but also by the force balance between endothelial cells (EC) traction stresses and extracellular matrix (ECM) viscoelastic resistance. Studies conducted with in vitro angiogenesis assays demonstrated that decreasing ECM stiffness triggers an angiogenic switch that promotes organization of EC into tubular cords or pseudo-capillaries. Thus, mechano-sensitivity of EC with regard to proteases secretion, and notably matrix metalloproteinases (MMPs), should likely play a pivotal role in this switching mechanism. While most studies analysing strain regulation of MMPs used cell cultured on stretched membranes, this work focuses on MMP expression during self-assembly of EC into capillary-like structures within fibrin gels, i.e. on conditions that mimics more closely the in vivo cellular mechanical microenvironment. The activity of MMP-2 and MMP-9, two MMPs that have a pivotal role in capillaries formation, has been monitored in pace with the progressive elongation of EAhy926 cells that takes place during the emergence of cellular cords. We found an increase of the zymogen proMMP-2 that correlates with the initial stages of EC cords formation. However, MMP-2 was not detected. ProMMP-9 secretion decreased, with levels of MMP-9 kept at a rather low value. In order to analyse more precisely the observed differences of EAhy926 response on fibrin and plastic substrates, we proposed a theoretical model of the mechano-regulation of proMMP-2 activation in the presence of type 2 tissue inhibitor of MMPs (TIMP-2). Using association/dissociation rates experimentally reported for this enzymatic network, the model adequately describes the synergism of proMMP-2 and TIMP-2 strain activation during pseudo-capillary morphogenesis. All together, these results provide a first step toward a systems biology approach of angiogenesis mechano-regulation by cell-generated extracellular stresses and strains. Content Type Journal Article Category Regular Article Pages 1-20 DOI 10.1007/s10441-012-9147-3 Authors Minh-Uyen Dao Thi, Faculté de Médecine de Grenoble, DyCTiM team, UJF-Grenoble 1, CNRS, Laboratoire TIMC-IMAG UMR 5525, 38041 Grenoble, France Candice Trocmé, BEP/DBTP, CHU Albert Michallon, BP 217, 38043 Grenoble Cedex 9, France Marie-Paule Montmasson, Faculté de Médecine de Grenoble, DyCTiM team, UJF-Grenoble 1, CNRS, Laboratoire TIMC-IMAG UMR 5525, 38041 Grenoble, France Eric Fanchon, Faculté de Médecine de Grenoble, BCM team, UJF-Grenoble 1, CNRS, Laboratoire TIMC-IMAG UMR 5525, 38041 Grenoble, France Bertrand Toussaint, BEP/DBTP, CHU Albert Michallon, BP 217, 38043 Grenoble Cedex 9, France Philippe Tracqui, Faculté de Médecine de Grenoble, DyCTiM team, UJF-Grenoble 1, CNRS, Laboratoire TIMC-IMAG UMR 5525, 38041 Grenoble, France Journal Acta Biotheoretica Online ISSN 1572-8358 Print ISSN 0001-5342.Reading list | Discuss | Edit | Categorize |My bibliography
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A theoretical model is presented for pattern formation in an epithelium. The epithelial model consists of a thin, incompressible, viscoelastic membrane on an elastic foundation (substrate), with the component cells assumed to have active contractile properties similar to those of smooth muscle. The analysis includes the effects of large strains and material nonlinearity, and the governing equations were solved using finite differences. Deformation patterns form when the cells activate while lying on the descending limb of their total (active + passive) stress-stretch curve. Various one-dimensional and two-dimensional simulations illustrate the effects of spatial and temporal variations in passive stiffness, as well as the effects of foundation stiffness and stretch activation. The model can be used to examine the mechanical aspects of pattern formation in morphogenetic processes such as angiogenesis and myocardial trabeculation.
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| | Scholar | At my library | More options ... In order to accomplish the transition from avascular to vascular growth, solid tumours secrete a diffusible substance known as tumour angiogenesis factor (TAF) into the surrounding tissue. Endothelial cells which form the lining of neighbouring blood vessels respond to this chemotactic stimulus in a well-ordered sequence of events comprising, at minimum, of a degradation of their basement membrane, migration and proliferation. Capillary sprouts are formed which migrate towards the tumour eventually penetrating it and permitting vascular growth to take place. It is during this stage of growth that the insidious process of invasion of surrounding tissues can and does take place. A model mechanism for angiogenesis is presented which includes the diffusion of the TAF into the surrounding host tissue and the response of the endothelial cells to the chemotactic stimulus. Numerical simulations of the model are shown to compare very well with experimental observations. The subsequent vascular growth of the tumour is discussed with regard to a classical reaction-diffusion pre-pattern model.
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| | Scholar | At my library | More options ... Despite the recent progress in the description of the molecular mechanisms of proliferation and differentiation controls in vitro, the regulation of the homeostasis of normal stratified epithelia remains unclear in vivo. Computer simulation represents a powerful tool to investigate the complex field of cell proliferation regulation networks. It provides huge computation capabilities to test, in a dynamic in silico context, hypotheses about the many pathways and feedback loops involved in cell growth and proliferation controls.Our approach combines a model of cell proliferation and a spatial representation of cells in 2D using the Voronoi graph. The cell proliferation model includes intracellular (cyclins, Cyclin Dependent Kinases - CDKs, Retinoblastoma protein - Rb, CDK inhibitors) and extracellular controls (growth and differentiation factors, integrins). The Voronoi graph associates a polygon with every cell and the set of these polygons defines the tissue architecture. Thus, the model provides a quantitative model of extracellular signals and cell motility as a function of the neighborhood during time dependent simulations.
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| | Other links: dx.doi.org | Scholar | At my library | More options ... Traction forces developed by most cell types play a significant role in the spatial organisation of biological tissues. However, due to the complexity of cell-extracellular matrix interactions, these forces are quantitatively difficult to estimate without explicitly considering cell properties and extracellular mechanical matrix responses. Recent experimental devices elaborated for measuring cell traction on extracellular matrix use cell deposits on a piece of gel placed between one fixed and one moving holder. We formulate here a mathematical model describing the dynamic behaviour of the cell-gel medium in such devices. This model is based on a mechanical force balance quantification of the gel visco-elastic response to the traction forces exerted by the diffusing cells. Thus, we theoretically analyzed and simulated the displacement of the free moving boundary of the system under various conditions for cells and gel concentrations. This modelis then used as the theoretical basis of an experimental device where endothelial cells are seeded on a rectangular biogel of fibrin cast between two floating holders, one fixed and the other linked to a force sensor. From a comparison of displacement of the gel moving boundary simulated by the model and the experimental data recorded from the moving holder displacement, the magnitude of the traction forces exerted by the endothelial cell on the fibrin gel was estimated for different experimental situations. Different analytical expressions for the cell traction term are proposed and the corresponding force quantifications are compared to the traction force measurements reported for various kind of cells with the use of similar or different experimental devices.
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| | Other links: dx.doi.org | Scholar | At my library | More options ... How environmental mechanical forces affect cellular functions is a central problem in cell biology. Theoretical models of cellular biomechanics provide relevant tools for understanding how the contributions of deformable intracellular components and specific adhesion conditions at the cell interface are integrated for determining the overall balance of mechanical forces within the cell. We investigate here the spatial distributions of intracellular stresses when adherent cells are probed by magnetic twisting cytometry. The influence of the cell nucleus stiffness on the simulated nonlinear torque-bead rotation response is analyzed by considering a finite element multi-component cell model in which the cell and its nucleus are considered as different hyperelastic materials. We additionally take into account the mechanical properties of the basal cell cortex, which can be affected by the interaction of the basal cell membrane with the extracellular substrate. In agreement with data obtained on epithelial cells, the simulated behaviour of the cell model relates the hyperelastic response observed at the entire cell scale to the distribution of stresses and strains within the nucleus and the cytoskeleton, up to cell adhesion areas. These results, which indicate how mechanical forces are transmitted at distant points through the cytoskeleton, are compared to recent data imaging the highly localized distribution of intracellular stresses.
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| | Scholar | At my library | More options ... Endothelial cells, when cultured on gelled basement membrane matrix exert forces of tension through which they deform the matrix and at the same time they aggregate into clusters. The cells eventually form a network of cord-like structures connecting cell aggregates. In this network, almost all of the matrix has been pulled underneath the cell cords and cell clusters. This phenomenon has been proposed as a possible model for the growth and development of planar vascular systems in vitro. Our hypothesis is that the matrix is reorganized and the cellular networks form as a result of traction forces exerted by the cells on the matrix and the latter's elasticity. We construct and analyze a mathematical model based on this hypothesis and examine conditions necessary for the formation of the pattern. We show cell migration is not necessary for pattern formation and that isotropic, strain-stimulated traction is sufficient to form the observed patterns.
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| | Scholar | At my library | More options ... Abstract Flax seedlings grown in the absence of environmental stimuli, stresses and injuries do not form epidermal meristems in their hypocotyls. Such meristems do form when the stimuli are combined with a transient depletion of calcium. These stimuli include the “manipulation stimulus” resulting from transferring the seedlings from germination to growth conditions. If, after a stimulus, calcium depletion is delayed, meristem production is also delayed; in other words, the meristem-production instruction can be memorised. Memorisation includes both storage and recall of information. Here, we focus on information recall. We show that if the first transient calcium depletion is followed by a second transient depletion there is a new round of meristem production. We also show that if an excess of calcium follows calcium depletion, meristem production is blocked; but if the excess of calcium is in turn followed by another calcium depletion, again there is a new round of meristem production. The same stored information can thus be recalled repeatedly (at least twice). We describe a conceptual model that takes into account these findings. Content Type Journal Article Category Regular Article Pages 1-15 DOI 10.1007/s10441-012-9145-5 Authors Marie-Claire Verdus, Laboratoire AMMIS (Assemblages Moléculaires, Modélisation et Imagerie SIMS), CNRS (GDR DYCOEC), Faculté des Sciences et Techniques, Université de Rouen, 76821 Mont-Saint-Aignan Cedex, France Camille Ripoll, Laboratoire AMMIS (Assemblages Moléculaires, Modélisation et Imagerie SIMS), CNRS (GDR DYCOEC), Faculté des Sciences et Techniques, Université de Rouen, 76821 Mont-Saint-Aignan Cedex, France Vic Norris, Laboratoire AMMIS (Assemblages Moléculaires, Modélisation et Imagerie SIMS), CNRS (GDR DYCOEC), Faculté des Sciences et Techniques, Université de Rouen, 76821 Mont-Saint-Aignan Cedex, France Michel Thellier, Laboratoire AMMIS (Assemblages Moléculaires, Modélisation et Imagerie SIMS), CNRS (GDR DYCOEC), Faculté des Sciences et Techniques, Université de Rouen, 76821 Mont-Saint-Aignan Cedex, France Journal Acta Biotheoretica Online ISSN 1572-8358 Print ISSN 0001-5342.
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| | Other links: dx.doi.org | Scholar | At my library | More options ... Discussion of Minh-Uyen Dao Thi , Candice Trocmé , Marie-Paule Montmasson , Eric Fanchon , Bertrand Toussaint & Philippe Tracqui, Investigating Metalloproteinases MMP-2 and MMP-9 Mechanosensitivity to Feedback Loops Involved in the Regulation of In Vitro Angiogenesis by Endogenous Mechanical Stresses
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