Cell adhesion and cortex contractility determine cell patterning in the Drosophila retina

Hayashi and Carthew (Nature 431 [2004], 647) have shown that the packing of cone cells in the Drosophila retina resembles soap bubble packing, and that changing E- and N-cadherin expression can change this packing, as well as cell shape. The analogy with bubbles suggests that cell packing is driven by surface minimization. We find that this assumption is insufficient to model the experimentally observed shapes and packing of the cells based on their cadherin expression. We then consider a model in which adhesion leads to a surface increase, balanced by cell cortex contraction. Using the experimentally observed distributions of E- and N-cadherin, we simulate the packing and cell shapes in the wildtype eye. Furthermore, by changing only the corresponding parameters, this model can describe the mutants with different numbers of cells, or changes in cadherin expression.Comment: revised manuscript; 8 pages, 6 figures; supplementary information not include

Fibronectin matrix-mediated cohesion suppresses invasion of prostate cancer cells

<p>Abstract</p> <p>Background</p> <p>Invasion is an important early step in the metastatic cascade and is the primary cause of death of prostate cancer patients. In order to invade, cells must detach from the primary tumor. Cell-cell and cell-ECM interactions are important regulators of cohesion - a property previously demonstrated to mediate cell detachment and invasion. The studies reported here propose a novel role for α5β1 integrin - the principle mediator of fibronectin matrix assembly (FNMA) - as an invasion suppressor of prostate cancer cells.</p> <p>Methods</p> <p>Using a combination of biophysical and cell biological methods, and well-characterized prostate cancer cell lines of varying invasiveness, we explore the relationship between cohesion, invasiveness, and FNMA.</p> <p>Results</p> <p>We show that cohesion is inversely proportional to invasive capacity. We also show that more invasive cells express lower levels of α5β1 integrin and lack the capacity for FNMA. Cells were generated to over-express either wild-type α5 integrin or an integrin in which the cytoplasmic domain of α5 was replaced with that of α2. The α2 construct does not promote FNMA. We show that only wild-type α5 integrin promotes aggregate compaction, increases cohesion, and reduces invasion of the more aggressive cells, and that these effects can be blocked by the 70-kDa fibronectin fragment.</p> <p>Conclusions</p> <p>We propose that restoring capacity for FNMA in deficient cells can increase tumor intercellular cohesion to a point that significantly reduces cell detachment and subsequent invasion. In prostate cancer, this could be of therapeutic benefit by blocking an early key step in the metastatic cascade.</p

Undulation Instability of Epithelial Tissues

Treating the epithelium as an incompressible fluid adjacent to a viscoelastic stroma, we find a novel hydrodynamic instability that leads to the formation of protrusions of the epithelium into the stroma. This instability is a candidate for epithelial fingering observed in vivo. It occurs for sufficiently large viscosity, cell-division rate and thickness of the dividing region in the epithelium. Our work provides physical insight into a potential mechanism by which interfaces between epithelia and stromas undulate, and potentially by which tissue dysplasia leads to cancerous invasion.Comment: 4 pages, 3 figure

Aspiration of biological viscoelastic drops

Spherical cellular aggregates are in vitro systems to study the physical and biophysical properties of tissues. We present a novel approach to characterize the mechanical properties of cellular aggregates using micropipette aspiration technique. We observe an aspiration in two distinct regimes, a fast elastic deformation followed by a viscous flow. We develop a model based on this viscoelastic behavior to deduce the surface tension, viscosity, and elastic modulus. A major result is the increase of the surface tension with the applied force, interpreted as an effect of cellular mechanosensing.Comment: 4 pages, 4 figures

Scaling of Traction Forces with Size of Cohesive Cell Colonies

To understand how the mechanical properties of tissues emerge from interactions of multiple cells, we measure traction stresses of cohesive colonies of 1-27 cells adherent to soft substrates. We find that traction stresses are generally localized at the periphery of the colony and the total traction force scales with the colony radius. For large colony sizes, the scaling appears to approach linear, suggesting the emergence of an apparent surface tension of order 1E-3 N/m. A simple model of the cell colony as a contractile elastic medium coupled to the substrate captures the spatial distribution of traction forces and the scaling of traction forces with the colony size.Comment: 5 pages, 3 figure

Kinetic Monte Carlo and Cellular Particle Dynamics Simulations of Multicellular Systems

Computer modeling of multicellular systems has been a valuable tool for interpreting and guiding in vitro experiments relevant to embryonic morphogenesis, tumor growth, angiogenesis and, lately, structure formation following the printing of cell aggregates as bioink particles. Computer simulations based on Metropolis Monte Carlo (MMC) algorithms were successful in explaining and predicting the resulting stationary structures (corresponding to the lowest adhesion energy state). Here we present two alternatives to the MMC approach for modeling cellular motion and self-assembly: (1) a kinetic Monte Carlo (KMC), and (2) a cellular particle dynamics (CPD) method. Unlike MMC, both KMC and CPD methods are capable of simulating the dynamics of the cellular system in real time. In the KMC approach a transition rate is associated with possible rearrangements of the cellular system, and the corresponding time evolution is expressed in terms of these rates. In the CPD approach cells are modeled as interacting cellular particles (CPs) and the time evolution of the multicellular system is determined by integrating the equations of motion of all CPs. The KMC and CPD methods are tested and compared by simulating two experimentally well known phenomena: (1) cell-sorting within an aggregate formed by two types of cells with different adhesivities, and (2) fusion of two spherical aggregates of living cells.Comment: 11 pages, 7 figures; submitted to Phys Rev

Fibronectin Matrix Assembly Suppresses Dispersal of Glioblastoma Cells

Glioblastoma (GBM), the most aggressive and most common form of primary brain tumor, has a median survival of 12–15 months. Surgical excision, radiation and chemotherapy are rarely curative since tumor cells broadly disperse within the brain. Preventing dispersal could be of therapeutic benefit. Previous studies have reported that increased cell-cell cohesion can markedly reduce invasion by discouraging cell detachment from the tumor mass. We have previously reported that α5β1 integrin-fibronectin interaction is a powerful mediator of indirect cell-cell cohesion and that the process of fibronectin matrix assembly (FNMA) is crucial to establishing strong bonds between cells in 3D tumor-like spheroids. Here, we explore a potential role for FNMA in preventing dispersal of GBM cells from a tumor-like mass. Using a series of GBM-derived cell lines we developed an in vitro assay to measure the dispersal velocity of aggregates on a solid substrate. Despite their similar pathologic grade, aggregates from these lines spread at markedly different rates. Spreading velocity is inversely proportional to capacity for FNMA and restoring FNMA in GBM cells markedly reduces spreading velocity by keeping cells more connected. Blocking FNMA using the 70 KDa fibronectin fragment in FNMA-restored cells rescues spreading velocity, establishing a functional role for FNMA in mediating dispersal. Collectively, the data support a functional causation between restoration of FNMA and decreased dispersal velocity. This is a first demonstration that FNMA can play a suppressive role in GBM dispersal

Exponential Distribution of Locomotion Activity in Cell Cultures

In vitro velocities of several cell types have been measured using computer controlled video microscopy, which allowed to record the cells' trajectories over several days. On the basis of our large data sets we show that the locomotion activity displays a universal exponential distribution. Thus, motion resulting from complex cellular processes can be well described by an unexpected, but very simple distribution function. A simple phenomenological model based on the interaction of various cellular processes and finite ATP production rate is proposed to explain these experimental results.Comment: 4 pages, 3 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

A statistical approach to estimating the strength of cell-cell interactions under the differential adhesion hypothesis

International audienceBACKGROUND: The Differential Adhesion Hypothesis (DAH) is a theory of the organization of cells within a tissue which has been validated by several biological experiments and tested against several alternative computational models. RESULTS: In this study, a statistical approach was developed for the estimation of the strength of adhesion, incorporating earlier discrete lattice models into a continuous marked point process framework. This framework allows to describe an ergodic Markov Chain Monte Carlo algorithm that can simulate the model and reproduce empirical biological patterns. The estimation procedure, based on a pseudo-likelihood approximation, is validated with simulations, and a brief application to medulloblastoma stained by beta-catenin markers is given. CONCLUSION: Our model includes the strength of cell-cell adhesion as a statistical parameter. The estimation procedure for this parameter is consistent with experimental data and would be useful for high-throughput cancer studies