The ultimate goal of systems biology research is to establish an integrated multi-scale model of the liver. Such a model is created by predicting molecular behaviour in an organ context, as well as organ function via emerging information from cellular and molecular processes. This will ultimately enable the discovery of key mechanisms of liver organization, mainte-nance, regeneration, endogenous and xenobiotic liver metabolism, and liver disease.
To pursue this goal, the sub-network Hepatic Siusonid - HepatoSin will contribute a spatio-temporal model simulating the cellular, signaling, and morphogenetic mechanisms underlying the arrangement of hepatocytes in a sinusoidal layer of polarized and metabolically differentiated cells.
This model will be integrated with a mechanistic model describing the process of liver damage induced by inflammation and regeneration and with a model of the cellular networks that govern liver lipid and drug metabolism.
The interaction of hepatocytes with blood vessel endothelial cells is of critical importance for cell polarity, metabolic activity, detoxification and bile acid secretion. Furthermore, activated stellate cells proliferate vigorously, lose vitamin A and synthesize and secrete excess amounts of ECM and a cohort of factors for cell-cell communication. Factors released by inflammatory cells lead to trans-differentiation of stellate cells and hepatocytes into (myo)-fibroblasts with loss of hepatocyte polarity. Loss of normal tissue architecture results in loss of metabolic functions and thus impaired organ function. Center: The consortium will reconstitute the hepatic sinusoid in vitro using micro-patterning techniques. Left: Integrated multi-scale model. Top: Snapshot of a model simulating regeneration of a liver lobule from central necrosis after intoxication by CCl4, established in HepatoSys II.