20,688 research outputs found
Connective Tissue Growth Factor in Regulation of RhoA Mediated Cytoskeletal Tension Associated Osteogenesis of Mouse Adipose-Derived Stromal Cells
Background: Cytoskeletal tension is an intracellular mechanism through which cells convert a mechanical signal into a biochemical response, including production of cytokines and activation of various signaling pathways. Methods/Principal Findings: Adipose-derived stromal cells (ASCs) were allowed to spread into large cells by seeding them at a low-density (1,250 cells/cm 2), which was observed to induce osteogenesis. Conversely, ASCs seeded at a high-density (25,000 cells/cm 2) featured small cells that promoted adipogenesis. RhoA and actin filaments were altered by changes in cell size. Blocking actin polymerization by Cytochalasin D influenced cytoskeletal tension and differentiation of ASCs. To understand the potential regulatory mechanisms leading to actin cytoskeletal tension, cDNA microarray was performed on large and small ASCs. Connective tissue growth factor (CTGF) was identified as a major regulator of osteogenesis associated with RhoA mediated cytoskeletal tension. Subsequently, knock-down of CTGF by siRNA in ASCs inhibited this osteogenesis. Conclusions/Significance: We conclude that CTGF is important in the regulation of cytoskeletal tension mediated AS
Mechanical and Systems Biology of Cancer
Mechanics and biochemical signaling are both often deregulated in cancer,
leading to cancer cell phenotypes that exhibit increased invasiveness,
proliferation, and survival. The dynamics and interactions of cytoskeletal
components control basic mechanical properties, such as cell tension,
stiffness, and engagement with the extracellular environment, which can lead to
extracellular matrix remodeling. Intracellular mechanics can alter signaling
and transcription factors, impacting cell decision making. Additionally,
signaling from soluble and mechanical factors in the extracellular environment,
such as substrate stiffness and ligand density, can modulate cytoskeletal
dynamics. Computational models closely integrated with experimental support,
incorporating cancer-specific parameters, can provide quantitative assessments
and serve as predictive tools toward dissecting the feedback between signaling
and mechanics and across multiple scales and domains in tumor progression.Comment: 18 pages, 3 figure
Differential segregation in a cell-cell contact interface: the dynamics of the immunological synapse
Receptor-ligand couples in the cell-cell contact interface between a T cell and an antigen-presenting cell form distinct geometric patterns and undergo spatial rearrangement within the contact interface. Spatial segregation of the antigen and adhesion receptors occurs within seconds of contact, central aggregation of the antigen receptor then occurring over 1-5 min. This structure, called the immunological synapse, is becoming a paradigm for localized signaling. However, the mechanisms driving its formation, in particular spatial segregation, are currently not understood. With a reaction diffusion model incorporating thermodynamics, elasticity, and reaction kinetics, we examine the hypothesis that differing bond lengths (extracellular domain size) is the driving force behind molecular segregation. We derive two key conditions necessary for segregation: a thermodynamic criterion on the effective bond elasticity and a requirement for the seeding/nucleation of domains. Domains have a minimum length scale and will only spontaneously coalesce/aggregate if the contact area is small or the membrane relaxation distance large. Otherwise, differential attachment of receptors to the cytoskeleton is required for central aggregation. Our analysis indicates that differential bond lengths have a significant effect on synapse dynamics, i.e., there is a significant contribution to the free energy of the interaction, suggesting that segregation by differential bond length is important in cell-cell contact interfaces and the immunological synapse
The Glassy Wormlike Chain
We introduce a new model for the dynamics of a wormlike chain in an
environment that gives rise to a rough free energy landscape, which we baptise
the glassy wormlike chain. It is obtained from the common wormlike chain by an
exponential stretching of the relaxation spectrum of its long-wavelength
eigenmodes, controlled by a single stretching parameter. Predictions for
pertinent observables such as the dynamic structure factor and the
microrheological susceptibility exhibit the characteristics of soft glassy
rheology and compare favourably with experimental data for reconstituted
cytoskeletal networks and live cells. We speculate about the possible
microscopic origin of the stretching, implications for the nonlinear rheology,
and the potential physiological significance of our results.Comment: 12 pages, 8 figures. Minor correction
The consequence of substrates of large- scale rigidity on actin network tension in adherent cells
International audienceThere is compelling evidence that substrate stiffness affects cell adhesion as well as cytoskeleton organization and contractile activity. This work was designed to study the cytoskeletal contractile activity of cells plated on microposts of different stiffness using a numerical model simulating the intracellular tension of individual cells. We allowed cells to adhere onto micropost substrates of various rigidities and used experimental traction force data to infer cell contractility using a numerical model. The model discriminates between the influence of substrate stiffness on cell tension and shows that higher substrate stiffness leads to an increase in intracellular tension. The strength of this model is its ability to calculate the mechanical state of each cell in accordance to its individual cytoskeletal structure. This is achieved by regenerating a numerical cytoskeleton base
The role of the cytoskeleton in volume regulation and beading transitions in PC12 neurites
We present investigations on volume regulation and beading shape transitions
in PC12 neurites conducted using a flow-chamber technique. By disrupting the
cell cytoskeleton with specific drugs we investigate the role of its individual
components in the volume regulation response. We find that microtubule
disruption increases both swelling rate and maximum volume attained, but does
not affect the ability of the neurite to recover its initial volume. In
addition, investigation of axonal beading --also known as pearling
instability-- provides additional clues on the mechanical state of the neurite.
We conclude that the initial swelling phase is mechanically slowed down by
microtubules, while the volume recovery is driven by passive diffusion of
osmolites. Our experiments provide a framework to investigate the role of
cytoskeletal mechanics in volume homeostasis
Echinocyte Shapes: Bending, Stretching and Shear Determine Spicule Shape and Spacing
We study the shapes of human red blood cells using continuum mechanics. In
particular, we model the crenated, echinocytic shapes and show how they may
arise from a competition between the bending energy of the plasma membrane and
the stretching/shear elastic energies of the membrane skeleton. In contrast to
earlier work, we calculate spicule shapes exactly by solving the equations of
continuum mechanics subject to appropriate boundary conditions. A simple
scaling analysis of this competition reveals an elastic length which sets the
length scale for the spicules and is, thus, related to the number of spicules
experimentally observed on the fully developed echinocyte.Comment: Revtex, 27 pages, 8 figures; some minor change
Mechanisms of pattern formation during T cell adhesion
T cells form intriguing patterns during adhesion to antigen-presenting cells.
The patterns at the cell-cell contact zone are composed of two types of
domains, which either contain short TCR/MHCp receptor-ligand complexes or the
longer LFA-1/ICAM-1 complexes. The final pattern consists of a central TCR/MHCp
domain surrounded by a ring-shaped LFA-1/ICAM-1 domain, while the
characteristic pattern formed at intermediate times is inverted with TCR/MHCp
complexes at the periphery of the contact zone and LFA-1/ICAM-1 complexes in
the center. In this article, we present a statistical-mechanical model of cell
adhesion and propose a novel mechanism for the T cell pattern formation. Our
mechanism for the formation of the intermediate inverted pattern is based (i)
on the initial nucleation of numerous TCR/MHCp microdomains, and (ii) on the
diffusion of free receptors and ligands into the contact zone. Due to this
inward diffusion, TCR/MHCp microdomains at the rim of the contact zone grow
faster and form an intermediate peripheral ring for sufficiently large TCR/MHCp
concentrations. In agreement with experiments, we find that the formation of
the final pattern with a central TCR/MHCp domain requires active cytoskeletal
transport processes. Without active transport, the intermediate inverted
pattern seems to be metastable in our model, which might explain patterns
observed during natural killer (NK) cell adhesion. At smaller TCR/MHCp complex
concentrations, we observe a different regime of pattern formation with
intermediate multifocal TCR/MHCp patterns which resemble experimental patterns
found during thymozyte adhesion.Comment: 12 pages, 8 figure
Mechanical Stress Inference for Two Dimensional Cell Arrays
Many morphogenetic processes involve mechanical rearrangement of epithelial
tissues that is driven by precisely regulated cytoskeletal forces and cell
adhesion. The mechanical state of the cell and intercellular adhesion are not
only the targets of regulation, but are themselves likely signals that
coordinate developmental process. Yet, because it is difficult to directly
measure mechanical stress {\it in vivo} on sub-cellular scale, little is
understood about the role of mechanics of development. Here we present an
alternative approach which takes advantage of the recent progress in live
imaging of morphogenetic processes and uses computational analysis of high
resolution images of epithelial tissues to infer relative magnitude of forces
acting within and between cells. We model intracellular stress in terms of bulk
pressure and interfacial tension, allowing these parameters to vary from cell
to cell and from interface to interface. Assuming that epithelial cell layers
are close to mechanical equilibrium, we use the observed geometry of the two
dimensional cell array to infer interfacial tensions and intracellular
pressures. Here we present the mathematical formulation of the proposed
Mechanical Inverse method and apply it to the analysis of epithelial cell
layers observed at the onset of ventral furrow formation in the {\it
Drosophila} embryo and in the process of hair-cell determination in the avian
cochlea. The analysis reveals mechanical anisotropy in the former process and
mechanical heterogeneity, correlated with cell differentiation, in the latter
process. The method opens a way for quantitative and detailed experimental
tests of models of cell and tissue mechanics
Active Tension Network model suggests an exotic mechanical state realized in epithelial tissues.
Mechanical interactions play a crucial role in epithelial morphogenesis, yet understanding the complex mechanisms through which stress and deformation affect cell behavior remains an open problem. Here we formulate and analyze the Active Tension Network (ATN) model, which assumes that the mechanical balance of cells within a tissue is dominated by cortical tension and introduces tension-dependent active remodeling of the cortex. We find that ATNs exhibit unusual mechanical properties. Specifically, an ATN behaves as a fluid at short times, but at long times supports external tension like a solid. Furthermore, an ATN has an extensively degenerate equilibrium mechanical state associated with a discrete conformal - "isogonal" - deformation of cells. The ATN model predicts a constraint on equilibrium cell geometries, which we demonstrate to approximately hold in certain epithelial tissues. We further show that isogonal modes are observed in the fruit y embryo, accounting for the striking variability of apical areas of ventral cells and helping understand the early phase of gastrulation. Living matter realizes new and exotic mechanical states, the study of which helps to understand biological phenomena
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