(490c) Systemic Analysis of a Cellular Network Model of Liver Regeneration Reveals Potential Mechanisms of Regeneration Suppression

As the body’s main detoxifying organ, the liver is routinely exposed to high levels of toxic compounds. Mature liver cells therefore retain the unique ability to enter the cell cycle and regenerate lost mass following even severe injury without impairing liver function. This tightly controlled response to an experimentally repeatable stress gives an ideal process to study the dynamic function of the organ. Up to a certain point, the liver's regulatory network is able to compensate for imbalances in strength and altered timing of factors; this is exemplified by animal-to-animal variability in gene and protein expression. However, after some threshold or in some imbalanced conditions, the network is no longer able to compensate for de-regulation and regeneration is impaired. We have developed a computational model of liver regeneration which allows for investigation into how the timing and balance of factors should respond in healthy animals and how they can be de-regulated to suppress regeneration.

     A systems approach was taken to develop a computational model of cellular crosstalk during liver regeneration by integrating critical cellular interactions between non-parenchymal cells and hepatocytes identified from an extensive review of existing literature. Model parameters were fit using high-throughput protein measurements taken from wild-type mice over a time-course of the priming phase of regeneration following partial hepatecomy and from published data describing regeneration profiles. Local and global sensitivity analyses were performed to identify key model parameters affecting regeneration. Subsequent analysis of the model, focusing on those factors, revealed several principles governing the suppression of regeneration following partial hepatectomy. De-regulating pro-proliferative signals (by either reducing their relative strength or delaying their production) causes a delay in the initiation of regeneration, but ultimately no change in the total mass recovered. De-regulating the anti-proliferative signals (by either increasing their relative strength or increasing production rates) causes no changes to the initiation of regeneration, but leads ultimately to a decrease in total liver mass recovered. Inhibition of either pathway by itself is not enough to completely suppress regeneration; however, if both pathways are simultaneously de-regulated, regeneration can be completely suppressed. Additionally, the model implicates TGF-β produced by stellate cells along with decreased metabolic load as key factors causing the decreased regenerative response seen in one-lobe partial hepatectomies.

     This work is a key piece of parallel efforts within our lab to identify cell-type specific, intracellular regulatory network models from high-throughput gene expression, miRNA expression, transcription factor binding, and protein levels.  Future work to iteratively improve this model will include experimental investigation of model predictions and integration of intracellular transcriptional models into the framework of the cellular network model.

Research Support: R01 18873, T32 07463