Liver Regeneration in a Cartoon

Photo: Three dimensional model of a liver after intoxication

A three-dimensional representation
of the 3D liver model after
intoxication with carbon tretrachloride;

Researchers at the Interdisciplinary Centre for Bioinformatics in Leipzig (IZBI) and the French National Institute for Research in Computer Science and Control (INRIA) near Paris have started investigating liver regeneration using computer-based methods of systems biology. The team simulated the scenario after intoxication with carbon tetrachloride (CCl4) in mice - a typical animal model for paracetamol intoxication in humans - on the computer.

At first the scientists obtained a computer representation of an average liver lobule. They recorded parameters necessary to quantitatively characterize the static lobule architecture, such as the shape and orientation of the blood vessels, and the shape, orientation and spatial organization of the hepatocytes. These parameters were extracted using image processing methods that allow the full three-dimensional reconstruction of microscopic images of specially prepared serial tissue sections, followed by turning the three-dimensional patterns into numbers.

Then the team recorded the regeneration process in the liver lobules of mice. The animals were injected with the liver-damaging substance carbon tetrachloride, which results in the death of hepatocytes near the central vein of the liver lobule. To characterize the regeneration process quantitatively, the scientists introduced so-called process parameters. These parameters record when and where new hepatocytes are created and register their movements and alignment.

Finally, based on all these parameters a mathematical model was developed with which the spatial- temporal dynamics of individual hepatocytes and blood vessels could be simulated on a computer. With their computer model the scientists managed to identify previously unrecognized mechanisms during regeneration in liver lobules. As it turned out, the new cells do not just emerge at arbitrary locations within the lobule.

“Instead it quickly became evident that the spatio-temporal process can only function properly if the new hepatocytes align themselves along the sinusoids, the micro-blood vessels that traverse the liver lobule. It brings us closer to understand of the complex processes involved in liver regeneration,” explains Stefan Höhme, a member of the research-team. This observation on the basis of the computer model was subsequently confirmed on real liver lobules in a laboratory experiment.; Source: HepatoSys/Virtual Liver Network