Statistical Modelling of Cell Movement

In this paper we demonstrate an application of the unscented Kalman filter in the context of cell movement, using a model defined in terms of stochastic differential equations (SDEs)

Inference of the drivers of collective movement in two cell types: Dictyostelium and melanoma

Collective cell movement is a key component of many important biological processes, including wound healing, the immune response and the spread of cancers. To understand and influence these movements, we need to be able to identify and quantify the contribution of their different underlying mechanisms. Here, we define a set of six candidate models—formulated as advection–diffusion–reaction partial differential equations—that incorporate a range of cell movement drivers. We fitted these models to movement assay data from two different cell types: Dictyostelium discoideum and human melanoma. Model comparison using widely applicable information criterion suggested that movement in both of our study systems was driven primarily by a self-generated gradient in the concentration of a depletable chemical in the cells' environment. For melanoma, there was also evidence that overcrowding influenced movement. These applications of model inference to determine the most likely drivers of cell movement indicate that such statistical techniques have potential to support targeted experimental work in increasing our understanding of collective cell movement in a range of systems

A Model of Movement Coordinates in Motor Cortex: Posture-Dependent Changes in the Gain and Direction of Single Cell Tuning Curves

Central to the problem of elucidating the cortical mechanisms that mediate movement behavior is an investigation of the coordinate systems by which movement variables are encoded in the firing rates of individual motor cortical neurons. In the last decade, neurophysiologists have probed how the preferred direction of an individual motor cortical cell (as determined by a center-out task) will change with posture because such changes are useful for inferring underlying cordinates. However, while the importance of shifts in preferred direction is well-known and widely accepted, posture-dependent changes in the depth of modulation of a cell's tuning curve, i.e. gain changes, have not been similarly identified as a means of coordinate inference. This paper develops a vector field framework which, by viewing the preferred direction and the gain of a cell's tuning curve as dual components of a unitary response vector, can compute how each aspect of cell response covaries with posture as a function of the coordinate system in which a given cell is hypothesized to encode its movement information. This integrated approach leads to a model of motor cortical cell activity that codifies the following four observations: 1) cell activity correlates with hand movement direction, 2) cell activity correlates with hand movement speed, 3) preferred directions vary with posture, and 4) the modulation depth of tuning curves varies with posture. Finally, the model suggests general methods for testing coordinate hypotheses at the single cell level and example protocols arc simulated for three possible coordinate systems: Cartesian spatial, shoulder-centered, and joint angle.Defense Advanced Research Projects Agency (N00014-92-J-4015); Defense Advanced Research Projects Agency and the Office of Naval Research (N00014-95-1-0409); National Science Foundation (IRI-90-00530, IRI-97-20333); Office of Naval Research (N00014-91-J-4100, N00014-92-J-1309, N00014-94-l-0940, N00014-95-1-0657)

Functional Analysis of Spontaneous Cell Movement under Different Physiological Conditions

Cells can show not only spontaneous movement but also tactic responses to environmental signals. Since the former can be regarded as the basis to realize the latter, playing essential roles in various cellular functions, it is important to investigate spontaneous movement quantitatively at different physiological conditions in relation to cellular physiological functions. For that purpose, we observed a series of spontaneous movements by Dictyostelium cells at different developmental periods by using a single cell tracking system. Using statistical analysis of these traced data, we found that cells showed complex dynamics with anomalous diffusion and that their velocity distribution had power-law tails in all conditions. Furthermore, as development proceeded, average velocity and persistency of the movement increased and as too did the exponential behavior in the velocity distribution. Based on these results, we succeeded in applying a generalized Langevin model to the experimental data. With this model, we discuss the relation of spontaneous cell movement to cellular physiological function and its relevance to behavioral strategies for cell survival.Comment: Accepted to PLoS ON

Phosphorylation of TGB1 by protein kinase CK2 promotes barley stripe mosaic virus movement in monocots and dicots.

The barley stripe mosaic virus (BSMV) triple gene block 1 (TGB1) protein is required for virus cell-to-cell movement. However, little information is available about how these activities are regulated by post-translational modifications. In this study, we showed that the BSMV Xinjiang strain TGB1 (XJTGB1) is phosphorylated in vivo and in vitro by protein kinase CK2 from barley and Nicotiana benthamiana. Liquid chromatography tandem mass spectrometry analysis and in vitro phosphorylation assays demonstrated that Thr-401 is the major phosphorylation site of the XJTGB1 protein, and suggested that a Thr-395 kinase docking site supports Thr-401 phosphorylation. Substitution of Thr-395 with alanine (T395A) only moderately impaired virus cell-to-cell movement and systemic infection. In contrast, the Thr-401 alanine (T401A) virus mutant was unable to systemically infect N. benthamiana but had only minor effects in monocot hosts. Substitution of Thr-395 or Thr-401 with aspartic acid interfered with monocot and dicot cell-to-cell movement and the plants failed to develop systemic infections. However, virus derivatives with single glutamic acid substitutions at Thr-395 and Thr-401 developed nearly normal systemic infections in the monocot hosts but were unable to infect N. benthamiana systemically, and none of the double mutants was able to infect dicot and monocot hosts. The mutant XJTGB1T395A/T401A weakened in vitro interactions between XJTGB1 and XJTGB3 proteins but had little effect on XJTGB1 RNA-binding ability. Taken together, our results support a critical role of CK2 phosphorylation in the movement of BSMV in monocots and dicots, and provide new insights into the roles of phosphorylation in TGB protein functions

Patterns of cell movement within the Dictyostelium slug revealed by cell type-specific, surface labeling of living cells

There are cells acattered in the rear, prespore region of the Dictyostelium slug that share many of the properties of the prestalk cells and that are therefore called anterior-like cells (ALCs). By placing the gene encoding a cell surface protein under the control of an ALC-specific promoter and immunologically labeling the living cells, we analyze the movement of ALCs within the slug. There is a posterior to anterior cellular flow, and the ALCs change their movement pattern as they enter the prestalk zone. Prestalk cells are periodically shed from the migrating slug. They must be replaced if the correct ratio of prestalk to prespore cells is to be maintained, and we present evidence for the trans-differentiation of prespore into prestalk cells, with ALCs functioning as intermediates in the transition. The slug has, therefore, a surprisingly dynamic structure, both with respect to cellular differentiation and cell movement

Adult skeletal muscle stem cell migration is mediated by a blebbing/amoeboid mechanism

Adult skeletal muscle possesses a resident stem cell population called satellite cells which are responsible for tissue repair following damage. Satellite cell migration is crucial in promoting rapid tissue regeneration but is a poorly understood process. Furthermore, the mechanisms facilitating satellite cell movement have yet to be elucidated. Here the process of satellite cell migration has been investigated revealing that they undergo two distinct phases of movement; firstly under the basal lamina and then rapidly increasing their velocity when on the myofibre surface. Most significantly we show that satellite cells move using a highly dynamic blebbing based mechanism and not via lamellopodia mediated propulsion. We show that nitric oxide and non-canonical Wnt signalling pathways are necessary for regulating the formation of blebs and the migration of satellite cells. In summary, we propose that the formation of blebs and their necessity for satellite cell migration has significant implications in the future development of therapeutic regimes aimed at promoting skeletal muscle regeneration

A gradient method for the quantitative analysis of cell movement and tissue flow and its application to the analysis of multicellular Dictyostelium development

We describe the application of a novel image processing method, which allows quantitative analysis of cell and tissue movement in a series of digitized video images. The result is a vector velocity field showing average direction and velocity of movement for every pixel in the frame. We apply this method to the analysis of cell movement during different stages of the Dictyostelium developmental cycle. We analysed time-lapse video recordings of cell movement in single cells, mounds and slugs. The program can correctly assess the speed and direction of movement of either unlabelled or labelled cells in a time series of video images depending on the illumination conditions. Our analysis of cell movement during multicellular development shows that the entire morphogenesis of Dictyostelium is characterized by rotational cell movement. The analysis of cell and tissue movement by the velocity field method should be applicable to the analysis of morphogenetic processes in other systems such as gastrulation and neurulation in vertebrate embryos

Modelling cell movement and chemotaxis pseudopod based feedback

A computational framework is presented for the simulation of eukaryotic cell migration and chemotaxis. An empirical pattern formation model, based on a system of non-linear reaction-diffusion equations, is approximated on an evolving cell boundary using an Arbitrary Lagrangian Eulerian surface finite element method (ALE-SFEM). The solution state is used to drive a mechanical model of the protrusive and retractive forces exerted on the cell boundary. Movement of the cell is achieved using a level set method. Results are presented for cell migration with and without chemotaxis. The simulated behaviour is compared with experimental results of migrating Dictyostelium discoideum cells