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Computational modelling of the spatial-temporal organization during liver regeneration: a multi-scale approachDirk Drasdo, Stefan Höhme, Ulf-Dietrich Braumann Interdisciplinary Centre for Bioinformatics University of Leipzig Cooperation: Jan G. Hengstler Institute for Toxicology Medical Faculty of the University of Leipzig Jens Timmer Zentrum für Modellbildung University of Freiburg Jens-Peer Kuska IZBI University of Leipzig The understanding of liver function and dysfunction requires to unveil the interplay of the individual functional units on all levels of organization ranging from individual molecules to signal transduction, to gene-and metabolic networks, up to the spatial and functional pattern on the level of the tissue units such as liver lobules (Fig. 1) and liver lobes. An ongoing toxification of hepatocytes by alcohol or CCl4, for example, may eventually lead to a destruction of regions of the liver that involve many cells hence the failure or partial failure of the liver function in this case is a multi-cellular phenomenon. The mechanisms that are responsible for a failure of the capability to restore the architecture are largely unknown and hard to be accessed by experimental studies only, since the experimental possibility to track the time development of the multi-cellular processes within individual liver lobules is very limited. During liver regeneration after alcohol or CCl4 hepatocyte proliferation starts in the areas of the lobules surrounding the portal fields and then proceeds to the pericentral areas. The precise mechanisms and how they comply with the physical constraints is largely unknown. State of the art: The main focus of mathematical approaches relevant for understanding of the systems biology of the liver is on the signal transduction as well as on the genetic and metabolic regulation in individual cells. Most approaches focus on the modeling of the intracellular regulation in liver cells.  Figure 1: Organization of the liver lobule, demonstrating critical structures for modelling of liver
regeneration (from: Junqueira, Histology, New York, 2005). The spatio-temporal processes during liver regeneration with the yellow
region are modelled.
Problem: Currently, these models are not able to explain the organization principles of the three-dimensional architecture of the liver (see. Fig. 1 for a liver lobule) which is crucial since the architecture is inherently coupled to the liver function. In order to understand how liver damages come about and how regeneration processes act to repair those damages, the understanding of the cell function at the level of the single cell is not sufficient. Rather, the interplay of cells on a multicellular level must be understood. Idea: We use the synergistic potential of experiments and computational modeling on different time and length scales to simulate scenarios that explain the potential mechanisms during the spatial-temporal organization processes during liver regeneration within a multi-scale approach, in which each cell is presented as an individual unit (for review, see Galle et. al., 2006). This approach has proven useful to explain the growth dynamics in monolayers and multicellular spheroids (e.g., Drasdo and Höhme, 2005), single-layered epithelial cell systems (Drasdo and Löffler, 2001) and early development (Drasdo and Forgacs, 2000). For a direct comparison with experimental data we use image processing to quantify cross-sections of the liver that show the spatial architecture and the proliferation and apoptosis patterns. Results: Within the image processing unit at the IZBI the procedures developed for 3D-reconstruction of cervix carcinoma (Braumann et. al., 2005) are now used to obtain a picture of the full 3D-architecture of liver lobules. The individual liver lobules may be identified by Voronoi-tesselations from 2D-section as indicated in Fig. 2. Benefit: The regeneration of liver tissue after damage appears to be a complex superposition of various cytokine stimulations, cell transitions and structure organizations. The understanding of the organization processes during liver regeneration after alcohol and CCl4 induced liver damage should eventually permit to explore therapeutic concepts for the treatment of liver cirrhosis and, as a long-term perspective, make pre-selections of schedules and to reduce costs of clinical trials by use of computer simulations. Outlook: The growth and differentiation pattern should be also explored in-vitro under consideration of the cell shape that emerges from the cell-cell and cell-substrate interaction and from the active shape control of the cell (in cooperation with A. Bader, J. Galle, M. Löffler).
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