Rajanikanth Vadigepalli and Jan B. Hoek Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia PA, USA
Chronic alcohol intake is detrimental for the regenerative response to liver injury. 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. A better understanding of the mechanistic basis of this impairment has clinical implications for a wide range of ethanol-induced liver defects. 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. Our transcriptomics and genome-wide transcription factor binding studies thus far provided evidence that ethanol affects interactions between hepatocytes and non-parenchymal cells that are essential for a coordinated and integrated repair response. We developed a novel pattern analysis approach to analyze the high-throughput data sets to identify broad changes as well as subtle cell-type specific regulation. Most interestingly, we identified differential gene expression 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. Supported by NIH grant R01 AA018873.