A hallmark of chronic liver disease is the impairment of the liver’s innate regenerative ability. In this work we use a computational approach to unravel the principles underlying control of liver repair following an acute physiological challenge.
We used a mathematical model of inter- and intra-cellular interactions during liver regeneration to infer key molecular factors underlying the dysregulation of multiple regeneration modes, including delayed, suppressed, and enhanced regeneration. We used model analysis techniques to identify organizational principles governing the cellular regulation of liver regeneration. We fit our model to several published data sets of deficient regeneration in rats and healthy regeneration in humans, rats, and mice to predict differences in molecular regulation in disease states and across species.
Analysis of the computational model pointed to an important balance involving inflammatory signals and growth factors, largely produced by Kupffer cells and hepatic stellate cells, respectively. Our model analysis results also indicated an organizational principle of molecular regulation whereby production rate of molecules acted to induce coarse-grained control of signaling levels while degradation rate acted to induce fine-tuning control. We used this computational framework to investigate hypotheses concerning molecular regulation of regeneration across species and in several chronic disease states in rats, including fructose-induced steatohepatitis, alcoholic steatohepatitis, toxin-induced cirrhosis, and toxin-induced diabetes. Our results indicate that altered non-parenchymal cell activation is sufficient to explain deficient regeneration caused by multiple disease states. We also investigated liver regeneration across mammalian species. Our results suggest that non-invasive measures of liver regeneration taken at 30 days following resection could differentiate between several hypotheses about how human liver regeneration differs from rat regeneration.
Overall, our results provide a new computational platform integrating a wide range of experimental information, with broader utility in exploring the dynamic patterns of liver regeneration across species and over multiple chronic diseases.