Spatial -temporal modelling of tissue toxicity and regeneration
Systems biology approaches for spatial-temporal modelling of liver toxicity and regeneration allow identification of new key mechanisms. An example is the identification of daughter hepatocytes along liver sinusoids as an order-principle during liver regeneration (Höhme et al., 2010). Disturbing this mechanism compromises liver regeneration.
Fig. 1: Reconstruction of liver tissue from confocal laser scans. Immunostaining
of DPPIV (green), ICAM (red) as well as DAPI nuclear staining (blue), and confocal
laser scanning (B) microscopy allow reconstruction of sinusoidal
networks (E) and of complete liver lobules (A).
An advantage of this type of reconstruction is that the data can be used for
further calculations. For example, the percentage of the hepatocyte surface
that is in contact with another hepatocyte or with sinusoidal endothelial cells
can be quantified. Using these techniques, measurements of cell relevant aspects
of the liver microarchitecture can be performed.
Fig. 2: Centrilobular liver damage induced by administration of CCl4 to mice. Two days after intoxication, a central dead cell area is observed that can be clearly distinguished from the darker surviving cells. After four days the central dead cell area becomes smaller and is no longer visible after eight days. Experimentally determined process parameters, such as time resolved data on proliferation and cell death at certain positions of the liver lobule are required for establishment of the models (videos 1 and 2).
Video 1: Compromised liver regeneration without the order principle “oriented cell division”. The model visualised by this video contains all experimentally determined process parameters but not yet the new order principle “oriented cell division” (OCD). OCD means that daughter hepatocytes after cell division reorient themselves in the direction of the closest sinusoid. Deletion of OCD from the model compromises liver micro-architecture during the regeneration process.
Video 2: Regeneration with “oriented cell division”. After inclusion of OCD into the model, the simulation is in agreement with the experimentally determined data.
Fig. 3: Experimental validation of the order principle “oriented cell division”. Reconstruction of regenerating liver tissue where daughter cells have been visualised by BrdU incorporation (green nuclei). Daughter cells after mitosis are oriented in the direction of the closest sinusoid.
Video 3: Time lapse video of mouse hepatocytes co-cultivated with sinusoidal endothelial cells of the mouse liver. Hepatocytes migrate in the direction of the endothelial cells and try to maximize the contact surface.
Selected publications
Stefan Höhme*, Marc Brulport*, Alexander Bauer, Essam Bedawy, Wiebke Schormann, Rolf Gebhardt, Sebastian Zellmer, Michael Schwarz, Ernesto Bockamp, Tobias Timmel, Jan G. Hengstler+, Dirk Drasdo+, Cell alignment along micro-vessels as order principle to restore tissue architecture during liver regeneration: from experiment to virtual tissues and back, in revision, PNAS, 2009.
Brulport M, Schormann W, Bauer A, Hermes M, Elsner C, Hammersen FJ, Beerheide W, Spitkovsky D, Härtig W, Nussler A, Horn LC, Edelmann J, Pelz-Ackermann O, Petersen J, Kamprad M, von Mach M, Lupp A, Zulewski H, Hengstler JG: Fate of extrahepatic human stem and precursor cells after transplantation into mouse livers. Hepatology 2007;46:861-70.
- In vitro systems with hepatocytes; novel toxicity tests
- Spatial –temporal modelling of tissue toxicity and regeneration
- Carcinogenesis and tumour development
- Research for applied and regulatory toxicology