STEFAN HOEHME (3D MODEL OF DAMAGED LIVER LOBULE)
S. Hoehme et al., “Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration,” PNAS, 107:10371-76, 2010. Free F1000 Evaluation
Dirk Drasdo at INRIA Paris-Rocquencourt and colleagues have been trying for a number of years to turn experimental information into mathematical models that help explain how cells form functional tissue. Now they have used high-resolution images and three-dimensional reconstruction to generate an accurate 3-D computational model of liver regeneration, uncovering a previously unknown mechanism in the process.
Starting with mouse livers treated with carbon tetrachloride (which models acetaminophen damage), Drasdo’s team built computational models of how liver lobules regenerate after damage. Their early models, which factored in increased cell proliferation and direction of cell migration, failed to describe how cells colonized and repaired damaged areas. On a hunch, they programmed dividing hepatocytes to line up along the nearest blood vessel. This appeared to fix the model’s shortcomings, and the team asked their experimental colleagues whether the same thing happened in real lobules.
This “truly excellent integrative approach,” was able to suggest “a novel biological mechanism,” wrote F1000 Member Philip Maini in his evaluation. Drasdo says that this shows the value of models, even when applied to complex biological systems.
The next step is to model regeneration of whole mouse liver lobes, Drasdo says. The models will be validated using noninvasive imaging in humans, to understand how the liver regenerates following cirrhosis or acetaminophen overdose.
In this 3D computational model, the regeneration of a liver lobule following damage by carbon tetratchloride stops short of a full recovery, suggesting that a crucial mechanism had not been factored in. Video from Hoehme et al. 10.1073/pnas.0909374107
Successful RegenerationIt was only when the dividing hepatocytes in the model were programmed to line up along microvessels that the wound was closed and the lobule architecture restored, suggesting this hepatocyte-sinusoid alignment (HSA) is a novel mechanism for liver lobule regeneration. Video from Hoehme et al. 10.1073/pnas.0909374107