A systems biology pursuit for identifying control points to counteract chronic alcohol-mediated impairment of liver regeneration

Chronic alcohol intake is detrimental for the regenerative response of liver. The impaired regeneration response may increase susceptibility to persistent liver damage after acute liver injury in alcohol-dependent individuals... [ view full abstract ]

Chronic alcohol intake is detrimental for the regenerative response of liver. The impaired regeneration response may increase susceptibility to persistent liver damage after acute liver injury in alcohol-dependent individuals and thereby contribute to the onset of chronic liver disease. We pursue a systems biology strategy that combines multiscale network modeling with the analysis of functional genomics data sets at the single cell scale to develop a mechanistic understanding of the factors that drive the temporal progression and the coordination of the tissue repair responses across different cell types. Based on our transcriptomics and genome-wide transcription factor binding studies thus far, we identified differential gene regulation subclusters that appear to reflect responses specific for non-parenchymal cells, which were not evident from previously published analyses of whole tissue samples. Our ongoing single cell gene expression studies suggest that chronic ethanol consumption shifts the distribution of hepatic stellate cells across a defined set of molecular states, with consequences for the overall tissue response to injury. We evaluated the tissue-scale consequence of the ethanol-mediated shift in cellular functional states using a novel computational model of the cellular and molecular networks driving liver regeneration following partial hepatectomy. Our modeling studies suggest that the ethanol-mediated disruption of dynamic state transitions of multiple cell types are necessary to yield defective regeneration. We are presently testing the efficacy of microRNA-based interventions for resetting the distribution of hepatic stellate cell molecular states to rescue from ethanol-induced deficiencies in liver regeneration. Funding: R01 AA018873, T32 AA007463, F31 AA023445, F31 AA024969.