Supplementary Material

Modeling Multi-Cellular Behavior in Epidermal Tissue Homeostasis via Finite State Machines in Multi-Agent Systems

Thomas Sütterlin1, Simone Huber2, Hartmut Dickhaus1 and Niels Grabe1,*

1 Medical Informatics Department, Institute of Medical Biometry and Informatics, University Hospital Heidelberg, Im Neuenheimer Feld 305 and Hamamatsu Tissue Imaging and Analysis Center (TIGA), BIOQUANT, University Heidelberg, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany

2 Department of Informatics, Heilbronn University, Max-Planck-Str. 39, 74081 Heilbronn, Germany


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Cell Cycle Demo Files
The cellbehavioral model and the chart set file used for the cell cycle demonstration in video tutorial 6 can be downloaded here.
Episim Video Tutorials

For an easy introduction to the Episim Plattform comprising the Episim Modeller and the Episim Simulator we created a set of video tutorials in which most of the platform's functions are demonstrated.

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Episim Video Tutorial Abstracts
In the following we provide a brief abstract for each video tutorial. The abstracts can also be downloaded as pdf on the top of this side.

Tutorial 1: Introduction to Episim Modeller
Episim Modeller is introduced showing the situation after the very first start of the program without any modeling projects in the modeling workspace. It is demonstrated how to create the demo project. This demo project is used in some of the subsequent video tutorials to demonstrate the capabilities of Episim Modeller and the Episim Simulator respectively. Further, the Graphical Model Editor, the Function Library and the Variable-Sheet Editor are explained. These three subunits are the core tools for graphical cell behavioral modeling using the Episim Modeller. Finally, we introduce in this tutorial the Model File Navigator and the Outline Viewer which allow easy navigation through larger cell behavioral models.

Tutorial 2: Model Validation
Before a cell behavioral model can be translated into executable java code each model has to be validated. Moreover, the modeler can use this functionality to check the syntactical and in some aspects as well the semantical correctness of his model. This tutorial explains how to use model validation in Episim Modeller. Further, it is exemplified how the system reports syntactical and semantical errors to the user.

Tutorial 3: Model Transformation into Java Code
Executable java code can be generated from each cell behavioral model built with the Episim Modeller. This code is stored in a java code archive (jar-file) which in turn can be loaded by Episim Simulator. Before the transformation process can be started a model file which is used as starting point for the code generation has to be selected. In this context it is important to know that Episim Modeller offers the opportunity to included already created model files as submodels in other models. This allows to hierarchically structuring cell behavioral models. Usually, the model which is on top of the hierarchy has to be selected for code transformation. The other model files are then included in the transformation process automatically as long as they are part of the hierarchy. This tutorial shows the different steps necessary to get the java code archive after having finished the graphical specification of the cell behavioral model.

Tutorial 4: Introduction to Episim Simulator
The code archive containing the executable java code generated out of the graphical cell behavioral model can be loaded by Episim Simulator. This tool simulates the model in a multi-agent based environment. Every cell of the simulation is represented by an independent agent who is embedded in a continuous toroidal spatial environment. This spatial environment does not possess a predefined grid structure. Episim Simulator has been specifically designed for the simulation of human epidermis. This tutorial demonstrates how to load the code archive in the Episim Simulator. Further, the handling of the tissue morphology visualization window is illustrated. Lastly, we show how to start simulation and how to modify global simulation parameters at runtime of the simulation.

Tutorial 5: Using the available default charts in Episim Simulator
There are several default charts available in the Episim Simulator to visualize very general simulation results like e.g. the turnover time of the simulated tissue and the number of cells in various differentiation stages. A cell behavioral model has to be loaded before the default charts can be selected. The selection has to be made before the simulation is started. Selection at runtime of the simulation is not possible. The tutorial shows how the aforementioned default charts can be used to easily monitor and visualize the simulation output of the cell behavioral model.

Tutorial 6: Demonstration of different cell cycle models in Episim Simulator
The EPISIM Simulator allows the definition of so called 'chart sets'. A chart set is always associated with a particular cell behavioral model and usually comprises charts visualizing very specific aspects and simulation outputs of the model. A chart is defined by using the graphical user interface provided by EPISIM Simulator and an especially for this purpose developed easy script language. This tutorial shows how to load an already existing chart set. The shown charts visualize the cell cycle of a single cell which is tracked in the tissue. After the death of the tracked cell a new one is selected automatically by the simulation environment. In this case cells at a very early age are preferred. It is demonstrated how to switch between different cell cycle realizations (available in the demo model of EPISIM Modeller) by simply modifying one global simulation parameter at runtime of the simulation.

Tutorial 7: Episim Modeller - Steps to create an own model (part I)
This tutorial is the first part of four showing all necessary steps to create an own cell behavioral model using the Episim Modeller. It is shown how to create a new modeling project in an empty workspace. It is not possible to have more than one modeling project in a workspace. If there already is a modeling project in your currently used workspace please close and restart the Episim Modeller. Thereafter you have to choose another location where a new workspace will be created. After having successfully created a new modeling project a new model file is needed. This tutorial demonstrates the creation of a model file and the subsequent arrangement the available windows in the Episim Modeller in order to be able to work efficiently.

Tutorial 8: Episim Modeller - Steps to create an own model (part II)
After having completed the previous tutorial this one continues with an introduction to the Variable Sheet-Editor. It is shown how to define the cell types, the global tissue parameters and the cell properties of a cell behavioral model. A default value can be assigned to each global tissue parameter and cell property. Additionally for each cell property a maximum and a minimum value can be defined if needed. The Episim Simulator takes care that the value of a cell property stays in the range given by the maximum and the minimum. This is done only if either the maximum or the minimum value is different from zero.

Tutorial 9: Episim Modeller - Steps to create an own model (part III)
Tutorial 8 demonstrates the definition of all required cell types and different kinds of parameters. We go on in this tutorial to demonstrate how to graphically specify a cell behavioral model. Thereby, we focus on the placement of the different available model elements on the modeling pane and the definition of transitions between these elements. It is shown how to add multiple output ports to a 'Transition Choice' element in order to be able to branch to multiple different paths. Further, it is demonstrated how to specify a start and an end node which are required in each model file. Finally, the connection of a model element's output port with the input port of another model element's input port is shown.

Tutorial 10: Episim Modeller - Steps to create an own model (part IV)
The last tutorial of this series shows the definition of conditional expressions for either a 'Transition Choice' or a 'Transition Condition'. The former allows to branch to multiple paths on the basis of a cell property's value or the result of a mathematical expression. The latter offers the opportunity to branch in two different paths based on the evaluation of a Boolean expression. Finally, it is demonstrated how action strings in the 'state' model elements are defined. In this context it is shown how the Variable-Sheet Editor and the Function Library can be used for this purpose. Finally we elucidate the use of the predefined functions (available in the Function Library) using the example of cell division.