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Live Imaging and Computational Modelling of Tissue Growth and Tissue Regeneration in Drosophila

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Live Imaging and Computational Modelling of Tissue Growth and Tissue Regeneration in Drosophila Live Imaging and Computational Modelling of Tissue Growth and Tissue Regeneration in Drosophila Jamie Rickman 19th January 2015 Abstract Wound healing in the epithelium of the Drosophila wing imaginal disc is a regenerative process which is known to proceed via the assembly of a contractile actin cable that circumscribes the wound drawing the leading edge cells together in a characterstic rosette formation. Here we computation- ally explore various other biological and mechanical processes that are involved in tissue repair in Drosophila; the formation of dynamic actin protrusions that pull each other forward to close the wound; the active extrusion of dead cells from the wound site; and the effect of a global tension force operating on the tissue. In silico simulation results, using the vertex model of epithelial tissue, and in vivo data are compared. It is found that patterning of line tensions in wounded cells and cells neighbouring the wound can drive rosette formation and wound closure. Results from simulating a global tension force indicate this could recapitulate the initial expansion phase of wound healing seen in experiment. Contents 1 Introduction 2 1.1 Tissue regeneration . 2 1.2 Regenerative healing in Drosophila wing imaginal discs . 2 1.3 The mechanical drivers of epithelial wound healing in Drosophila . 3 2 The Vertex Model 4 3 Current work and results 5 3.1 Wound closure in vivo ...................................... 5 3.1.1 Wound closure rate . 5 3.1.2 Rosette formation . 5 3.1.3 Inital expansion of wound following ablation . 6 3.2 Wound Closure in silico ..................................... 7 3.2.1 Implementation of the vertex model . 7 3.2.2 Simulating actin protrusions . 8 3.2.3 Simulating extrusion of dying cells from the wound site using an equilibrium dy- namics approach . 9 3.2.4 Simulating a global tension force . 10 4 Discussion 11 5 Acknowlegdgements 12 1 1 Introduction 1.1 Tissue regeneration Tissue regeneration is a remarkable phenomenon and is as yet little understood. Immediately following tissue damage a variety of complex biological systems are activated that can repair a wound with no loss of function. This process requires precise synchronisation of complex intercellular and intracellular pathways that instigate dramatic changes; in cell phenotype, gene expression, differentiation and prolifer- ation. However there are stark differences in the capacity for regeneration across the animal kingdom and this remains a challenging question in developmental biology. Why is that a salamander can regenerate complex body parts and man cannot? Even more puzzling is the question of why a human foetus can perform this kind of regeneration but we lose the ability as adults. Non-regenerative wound repair often results in a mass of fibrotic tissue (a scar) and this poses a huge clinical burden. For example myocardial scar tissue caused by heart attacks is thought to contribute to congestive heart failure and arrhythmia and toxin-induced scarring in the liver is thought to lead to cirrhosis [1]. The ultimate aim of this field of study is to instingate the signalling pathways in adult human tissues that can lead to regeneration. Advances in nanotechnology and bioengineering bring this paradigm closer than ever, in which the biological microenvironment of a wound can be controlled at a patients bedside. Unravelling the coupling between biology and mechanics in wound healing is a necessary first step to understanding the molecular and cellular processes at play. The aim of this report is to investigate a computational model of wound healing based on the vertex model. A biological and physical under- standing will be bought to bear on the model and simulation results will be discussed and compared to experimental data. 1.2 Regenerative healing in Drosophila wing imaginal discs Drosophila is a holometabolous insect, undergoing four life stages from embryo to larva to pupa to adult. The dramatic metamorphoses that take place during these transitions make it a particularly interesting case for studying cell and tissue development. Drosophila can regenerate its tissue in a number of circumstances and is used here as a model organisn. This report looks in particular at regeneration of the wing imaginal disc. Discussion of the complex chemical signalling pathways that orchestrate wound healing in Drosophila lie outside the scope of this report [2],[3]. Here we will focus on the mechanotransduction of these chemical signals, the intrinsic mechanics of the wounded tissue and how the forces that result mediate regeneration. Following T. H. Morgan's definitions, a distinction must first be made between the morphallaxis of the Drosophila case and the epimorphosis of the salamander case. The former process is a remodelling of existing tissue to rebuild the tissue architecture while the latter involves the dedifferentiation of a cluster of mature cells in the wound environment that form a blastema which then redifferentiates and proliferates to replace missing tissue. While the epimorphosis of the salamander might seem a more relevant model system since it pertains to vertebrates, it has been found that the mechanisms involved in the morphollaxis of Drosophila are highly conserved across phylogeny. In both Drosophila wound repair and mammalian re-epithelialization the JUN amino terminal kinase signalling pathways are deployed [1]. And in embryonic wound repair, formation of an actomyosin cable and extension of actin structures (filopodia and lamellipodia) are seen in both cases [4]. This has motivated the use of Drosophila as a model system. The imaginal discs of the Drosophila have received particular attention [5], these are small clusters of cells in the insect larva that will develop into the integument and appendages of the adult body during pupation. They have a number of features that make them amenable to study on a genetic and physical basis; • Discs are composed of a single layer of columnar epithelium, with a peripodial epithelium contin- uous with the disc at its edges composed of flat squamous cells, see figure 1. Their cells remain undifferentiated until metamorphosis; this makes them easy to image. • Surgery and culture of imaginal discs is relatively simple. • Because of Drosophila's well known genetics the system is genetically tractable. Figure 1: Left: map of the wing disc showing anterior-posterior (AP) and dorsal-ventral (DV) compartment boundaries. Right: The three cell layers in the wing disc: the squamous epithelium or peripodial membrane, the columnar epithelium. Picture taken from [6]. 1.3 The mechanical drivers of epithelial wound healing in Drosophila Studies of wound healing in Drosophila have shown that there are two distinct mechanical processes that occur during tissue regeneration. 1. Localization of actomyosin resulting in the formation of an actin cable that circles the leading edge of the wound and acts like a `purse string' to pull the wound closed [7][8][9]. 2. Cells at the leading edge of the wound form actin protrusions, namely lamellipodia and filopodia. These protrusions tug on one another to pull cells at the leading edge forward. These two processes work can work in conjunction, with the balance between them determined by factors such as wound topology. For example it has been proposed that larger wounds close primarily by the action of lamellipodia whereas smaller wounds close via the actin cable mechanism. Conversely for small incisions actin cable assembly does not occur and opposing edges simply zip together via lamellipodial protrusions [8]. Following the work of Abreu et al., wound closing will be discussed as a four-stage process of 1) expansion, 2) coalescence, 3) contraction and 4) closure. The coalescence stage of closure occurs before the actin cable assembles (minutes after wounding), here wound size is relatively stable. Since the coalescence is too short for the up-regulation of actin to have occurred it is thought that re-organization of filamentous actin present in the cell or the polymerization of actin monomer takes place [10]. Intercellular segments of the cable are linked through adherens junc- tions between abutting cells. During the contraction phase the tightening of the actin cable leads to the formation of a characteristic rosette pattern, elongating cells at the wound edge and shortening their linked edges. As the wound tightens some cells at the leading edge are pushed backwards so the wound circumference decreases [8]. The increased cortical tension at these edges has been established through laser ablation experiments. A positive feedback loop, whereby increased tension is sustained and gener- ated by actomyosin localization has been suggested [7]. Previous work from this lab [11] investigating the upregulation of actomyosin found that this process has a characteristic time course, see figure 9b. Lamellipodial protrusions in the apical layer of leading edge cells have been observed during wound heal- ing in Drosophila. Although lamellipodial crawling, whereby leading edge cells pull themselves forward using these protrusions, has been more commonly associated with adult tissue [3], a combination of both this and the actin cable mechanism have been reported in the wing imaginal disc [12]. In the final closure stage both dynamic filopodia and lamellipodia have been observed to protrude from the leading edge cells and perform the final knitting together of the wound [13][8]. Gene knockout experiments have been performed to investigate the action of each mechanism in isola- tion. Mutant Drosophila embryos for Cdc42, a GTPase that regulates formation of actin protrusions, have been shown to be unable to perform the final closing stage, wounds are seen to stabilize. Conversely mutants for Rho1 (necessary for actin cable formation) are able to fully close the wound via actin pro- trusions, with a rate of contraction similar to wild type. The coalescence phase is much longer however, this could be due to the disorganised leading edge not being brought into line by the contractile action of the actin cable.
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