177 research outputs found
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A systems biology approach to multi-scale modelling and analysis of planar cell polarity in drosophila melanogaster wing
This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Systems biology aims to describe and understand biology at a global scale where biological systems function as a result of complex mechanisms that happen at several scales. Modelling and simulation are computational tools that are invaluable for description, understanding and prediction these mechanisms in a quantitative and integrative way. Thus multi-scale methods that couple the design, simulation and analysis of models spanning several spatial and temporal scales is becoming a new emerging focus of systems biology. This thesis uses an exemplar – Planar cell polarity (PCP) signalling – to illustrate a generic approach to model biological systems at different spatial scales, using the new concept of Hierarchically Coloured Petri Nets (HCPN). PCP signalling refers to the coordinated polarisation of cells within the plane of various epithelial tissues to generate sub-cellular asymmetry along an axis orthogonal to their apical-basal axes. This polarisation is required for many developmental events in both vertebrates and non-vertebrates. Defects in PCP in vertebrates are responsible for developmental abnormalities in multiple tissues including the neural tube, the kidney and the inner ear. In Drosophila wing, PCP is seen in the parallel orientation of hairs that protrude from each of the approximately 30,000 epithelial cells to robustly point toward the wing tip. This work applies HCPN to model a tissue comprising multiple cells hexagonally packed in a honeycomb formation in order to describe the phenomenon of Planar Cell Polarity (PCP) in Drosophila wing. HCPN facilitate the construction of mathematically tractable, compact and parameterised large-scale models. Different levels of abstraction that can be used in order to simplify such a complex system are first illustrated. The PCP system is first represented at an abstract level without modelling details of the cell. Each cell is then sub-divided into seven virtual compartments with adjacent cells being coupled via the formation of intercellular complexes. A more detailed model is later developed, describing the intra- and inter-cellular signalling mechanisms involved in PCP signalling. The initial model is for a wild-type organism, and then a family of related models, permitting different hypotheses to be explored regarding the mechanisms underlying PCP, are constructed. Among them, the largest model consists of 800 cells which when unfolded yields 164,000 places (each of which is described by an ordinary differential equation). This thesis illustrates the power and validity of the approach by showing how the models can be easily adapted to describe well-documented genetic mutations in the Drosophila wing using the proposed approach including clustering and model checking over time series of primary and secondary data, which can be employed to analyse and check such multi-scale models similar to the case of PCP. The HCPN models support the interpretation of biological observations reported in literature and are able to make sensible predictions. As HCPN model multi-scale systems in a compact, parameterised and scalable way, this modelling approach can be applied to other large-scale or multi-scale systems.This study was funded by Brunel University
Toward high-content/high-throughput imaging and analysis of embryonic morphogenesis
In vivo study of embryonic morphogenesis tremendously benefits from recent advances in live microscopy and computational analyses. Quantitative and automated investigation of morphogenetic processes opens the field to high-content and high-throughput strategies. Following experimental workflow currently developed in cell biology, we identify the key challenges for applying such strategies in developmental biology. We review the recent progress in embryo preparation and manipulation, live imaging, data registration, image segmentation, feature computation, and data mining dedicated to the study of embryonic morphogenesis. We discuss a selection of pioneering studies that tackled the current methodological bottlenecks and illustrated the investigation of morphogenetic processes in vivo using quantitative and automated imaging and analysis of hundreds or thousands of cells simultaneously, paving the way for high-content/high-throughput strategies and systems analysis of embryonic morphogenesis
Structural characterization and statistical-mechanical model of epidermal patterns
In proliferating epithelia of mammalian skin, cells of irregular
polygonal-like shapes pack into complex nearly flat two-dimensional structures
that are pliable to deformations. In this work, we employ various sensitive
correlation functions to quantitatively characterize structural features of
evolving packings of epithelial cells across length scales in mouse skin. We
find that the pair statistics in direct and Fourier spaces of the cell
centroids in the early stages of embryonic development show structural
directional dependence, while in the late stages the patterns tend towards
statistically isotropic states. We construct a minimalist four-component
statistical-mechanical model involving effective isotropic pair interactions
consisting of hard-core repulsion and extra short-ranged soft-core repulsion
beyond the hard core, whose length scale is roughly the same as the hard core.
The model parameters are optimized to match the sample pair statistics in both
direct and Fourier spaces. By doing this, the parameters are biologically
constrained. Our model predicts essentially the same polygonal shape
distribution and size disparity of cells found in experiments as measured by
Voronoi statistics. Moreover, our simulated equilibrium liquid-like
configurations are able to match other nontrivial unconstrained statistics,
which is a testament to the power and novelty of the model. We discuss ways in
which our model might be extended so as to better understand morphogenesis (in
particular the emergence of planar cell polarity), wound-healing, and disease
progression processes in skin, and how it could be applied to the design of
synthetic tissues
The Role of Intracellular Interactions in the Collective Polarization of Tissues and its Interplay with Cellular Geometry
Planar cell polarity (PCP), the coherent in-plane polarization of a tissue on
multicellular length scales, provides directional information that guides a
multitude of developmental processes at cellular and tissue levels. While it is
manifest that cells utilize both intracellular and intercellular mechanisms,
how the two produce the collective polarization remains an active area of
investigation. We study the role of intracellular interactions in the
large-scale spatial coherence of cell polarities, and scrutinize the role of
intracellular interactions in the emergence of tissue-wide polarization. We
demonstrate that nonlocal cytoplasmic interactions are necessary and sufficient
for the robust long-range polarization, and are essential to the faithful
detection of weak directional signals. In the presence of nonlocal
interactions, signatures of geometrical information in tissue polarity become
manifest. We investigate the deleterious effects of geometric disorder, and
determine conditions on the cytoplasmic interactions that guarantee the
stability of polarization. These conditions get progressively more stringent
upon increasing the geometric disorder. Another situation where the role of
geometrical information might be evident is elongated tissues. Strikingly, our
model recapitulates an observed influence of tissue elongation on the
orientation of polarity. Eventually, we introduce three classes of mutants:
lack of membrane proteins, cytoplasmic proteins, and local geometrical
irregularities. We adopt core-PCP as a model pathway, and interpret the model
parameters accordingly, through comparing the in silico and in vivo phenotypes.
This comparison helps us shed light on the roles of the cytoplasmic proteins in
cell-cell communication, and make predictions regarding the cooperation of
cytoplasmic and membrane proteins in long-range polarization.Comment: 15 pages Main Text + 8 page Appendi
A node-based version of the cellular Potts model
The cellular Potts model (CPM) is a lattice-based Monte Carlo method that uses an energetic formalism to describe the phenomenological mechanisms underlying the biophysical problem of interest. We here propose a CPM-derived framework that relies on a node-based representation of cell-scale elements. This feature has relevant consequences on the overall simulation environment. First, our model can be implemented on any given domain, provided a proper discretization (which can be regular or irregular, fixed or time evolving). Then, it allowed an explicit representation of cell membranes, whose displacements realistically result in cell movement. Finally, our node-based approach can be easily interfaced with continuous mechanics or fluid dynamics models. The proposed computational environment is here applied to some simple biological phenomena, such as cell sorting and chemotactic migration, also in order to achieve an analysis of the performance of the underlying algorithm. This work is finally equipped with a critical comparison between the advantages and disadvantages of our model with respect to the traditional CPM and to some similar vertex-based approaches
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Coloured Petri nets for multi-level, multiscale, and multi-dimensional modelling of biological systems
Owing to the availability of data of one biological phenomenon at different levels/scales, modelling of biological systems is moving from single level/scale to multiple levels/scales, which introduces a number of challenges. Coloured Petri nets (ColPNs) have been successfully applied to multilevel, multiscale and multidimensional modelling of some biological systems, addressing many of these challenges. In this article, we first review the basics of ColPNs and some popular extensions, and then their applications for multilevel, multiscale and multidimensional modelling of biological systems. This understanding of how to use ColPNs for modelling biological systems will assist readers in selecting appropriate ColPN classes for specific modelling circumstances
BMP/Dpp signaling and epithelial morphogenesis in Drosophila development
In this thesis, I mainly investigate how BMP/Dpp signaling is involved in development of the early pupal wing of Drosophila, and the mechanisms coupling Dpp signaling with morphogenesis.Tässä työssä tutkitaan lähinnä sitä, miten BMP / Dpp-signalointi on mukana Drosophilan varhaisen pupalin siiven kehityksessä ja mekanismeja, jotka kytkeytyvät Dpp-signalointiin morfogeneesi kanssa
Anisotropy links cell shapes to tissue flow during convergent extension
Within developing embryos, tissues flow and reorganize dramatically on
timescales as short as minutes. This includes epithelial tissues, which often
narrow and elongate in convergent extension movements due to anisotropies in
external forces or in internal cell-generated forces. However, the mechanisms
that allow or prevent tissue reorganization, especially in the presence of
strongly anisotropic forces, remain unclear. We study this question in the
converging and extending Drosophila germband epithelium, which displays planar
polarized myosin II and experiences anisotropic forces from neighboring
tissues, and we show that in contrast to isotropic tissues, cell shape alone is
not sufficient to predict the onset of rapid cell rearrangement. From
theoretical considerations and vertex model simulations, we predict that in
anisotropic tissues two experimentally accessible metrics of cell patterns, the
cell shape index and a cell alignment index, are required to determine whether
an anisotropic tissue is in a solid-like or fluid-like state. We show that
changes in cell shape and alignment over time in the Drosophila germband
predict the onset of rapid cell rearrangement in both wild-type and snail twist
mutant embryos, where our theoretical prediction is further improved when we
also account for cell packing disorder. These findings suggest that convergent
extension is associated with a transition to more fluid-like tissue behavior,
which may help accommodate tissue shape changes during rapid developmental
events
Coupling between dynamic 3D tissue architecture and BMP morphogen signaling during Drosophila wing morphogenesis
At the level of organ formation, tissue morphogenesis drives developmental processes in animals, often involving the rearrangement of two-dimensional (2D) structures into more complex three-dimensional (3D) tissues. These processes can be directed by growth factor signaling pathways. However, little is known about how such morphological changes affect the spatiotemporal distribution of growth factor signaling. Here, using the Drosophila pupal wing, we address how decapentaplegic (Dpp)/bone morphogenetic protein (BMP) signaling and 3D wing morphogenesis are coordinated. Dpp, expressed in the longitudinal veins (LVs) of the pupal wing, initially diffuses laterally within both dorsal and ventral wing epithelia during the inflation stage to regulate cell proliferation. Dpp localization is then refined to the LVs within each epithelial plane, but with active interplanar signaling for vein patterning/differentiation, as the two epithelia appose. Our data further suggest that the 3D architecture of the wing epithelia and the spatial distribution of BMP signaling are tightly coupled, revealing that 3D morphogenesis is an emergent property of the interactions between extracellular signaling and tissue shape changes.Peer reviewe
Impact of implementation choices on quantitative predictions of cell-based computational models
‘Cell-based’ models provide a powerful computational tool for studying the mechanisms
underlying the growth and dynamics of biological tissues in health and disease. An
increasing amount of quantitative data with cellular resolution has paved the way for
the quantitative parameterisation and validation of such models. However, the numerical
implementation of cell-based models remains challenging, and little work has been done to
understand to what extent implementation choices may influence model predictions. Here,
we consider the numerical implementation of a popular class of cell-based models called
vertex models, which are often used to study epithelial tissues. In two-dimensional vertex
models, a tissue is approximated as a tessellation of polygons and the vertices of these
polygons move due to mechanical forces originating from the cells. Such models have been
used extensively to study the mechanical regulation of tissue topology in the literature.
Here, we analyse how the model predictions may be affected by numerical parameters,
such as the size of the time step, and non-physical model parameters, such as length
thresholds for cell rearrangement. We find that vertex positions and summary statistics
are sensitive to several of these implementation parameters. For example, the predicted
tissue size decreases with decreasing cell cycle durations, and cell rearrangement may
be suppressed by large time steps. These findings are counter-intuitive and illustrate that
model predictions need to be thoroughly analysed and implementation details carefully
considered when applying cell-based computational models in a quantitative setting
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