Computational Modeling of Vesicle-Mediated Cell Transport

The particularly important characteristics of eukaryotic cells are the enormous complexity of their membrane anatomy and the high level of organization of the transport processes. The surprisingly precise manner of the routing of vesicles to various intracellular and extracellular destinations can be illustrated by numerous examples such as the release of neurotransmitters into the presynaptic region of a nerve cell and the export of insulin to the cell surface. The key idea of the present project is to couple results of biomedical investigations and mechano-mathematical models with the highly efficient engineering software packages in order to simulate this type of processes, in particular the vesicle transport. The results should bridge the theoretical investigations and medical praxis and shift the paradigm in understanding and remedying different diseases, which certainly is the primary and long-term goal of the project. The individual objectives coincide with the modeling of single aspects of the vesicle transport, namely with the simulation of mechanisms by which the vesicles form, find their correct destination, fuse with organelles and deliver their cargo. The application of several different approaches is envisaged for this purpose, but three main strategies build the underlying skeleton: the theory of lipid bilayer membranes, the homogenization method and the diffusion theory. The mentioned approaches will furthermore be combined with the modern numerical techniques such as the finite element method and the multiscale finite element method. In the final stage, the realization of single objectives will allow the simulation of vesicle transport as a continuous process and the study of the impact of various factors on the whole process. This way, the project will yield a significant shift from "static" bio-computations related to the single cell compartments and substeps of its activities, to the "dynamic" simulation of the real living processes.

Many vital processes in our eukaryotic cells and organs, such as the metabolism, temporary storage and transport of nutrients, enzymes and transmitters, or viral entry into cells, require an astonishingly precise routing of intermediate products on various intra- and extracellular pathways, using spherical vesicles as protective transporter capsules. To better understand the role of this vesicle-mediated transport in relation to the initiation and progression of important neurological, immunological and cardiovascular diseases, it is essential to identify the biological factors that favor and limit them, which requires various expensive lab experiments. Therefore, by coupling the insights from biomedical investigations and mechano-mathematical models with highly efficient software packages, the CM-TransCell project aimed to minimize the number of future experiments by generating promising hypotheses based on numerous computer simulations. However, many facets of such intracellular processes are not yet experimentally accessible because they occur at the nanoscale level and have short process times, which strengthens the role of numerical simulation tools. However, realistic modeling of vesicle-mediated cell transport requires considering the highly complex intracellular composition, the related mechanical environment, and relevant biophysical properties. The inside of a eukaryotic cell is densely packed with numerous structural scaffoldings (cross-linked filaments and membranes) surrounded by a viscous fluid that impedes vesicle motion. Experiments indicate that vesicles either slowly diffuse inside the fluid or are quickly carried along filaments once they come into contact with motor proteins. Both transport mechanisms and the viscoelastic filament features were incorporated into a novel multiscale computer model of a eukaryotic cell, which made it possible to investigate numerically how different specific alterations at the filament level (e.g., filament density, porosity, orientation distribution due to changed mechanical stimulations or genetic disorders, the vesicle size, etc.) affect the macroscopic transport. For example, the simulations have shed light on the essential compensatory role of rapid vesicle transport via motor proteins. With significantly increased filament densities, the diffusive vesicle transport would critically slowed down and tus have a negative impact on essential physiological cell and tissue maintenance processes. Other numerical concepts developed within the project make it possible to obtain information about virus entry into a cell under various scenarios. The viral uptake process could be investigated by estimating virus-specific parameters, which is not accessible otherwise when using current experimental methods. This enabled the required process time and its limiting behavior to be investigated for the first time. The results obtained within the project unanimously confirm the great potential of numerical simulation tools to study various cellular activities and their clinical relevance. However, validation of the proposed hypotheses and optimization of the computer models are identified as the main challenges for future work.