Partial Hepatectomy as a Model of Liver Regeneration: Network-Based Profiles
Abstract
Liver disease is one of the leading causes of death worldwide, with comorbidities that are becoming more widespread each year and stagnant progress in the development of therapeutic interventions. Computational modeling is poised to provide much needed improvements to the use of gold standard interventions like liver resection and living donor transplantation, which rely on the liver’s ability to regenerate a significant portion of its mass. By expanding the reliability of models of liver regeneration to simulate clinically relevant scenarios, such computational tools could improve the efficacy of regeneration-based treatments and increase the number of donors and patients who could benefit from these procedures. Presented here is an integrative approach utilizing multi-scale and multi-modal data analysis to uncover systemic principles that guide both healthy liver regrowth after a 70% partial hepatectomy and how this process is impaired by chronic ethanol intake. The first tier of this work shows the coincidence of increased blood flow through the portal vein and impaired regeneration using a series of non-invasive ultrasound methods to make quantitative observations about organ-scale physiology in rats subjected to partial hepatectomy. Computational modeling based on the observed organ-scale data reveals sex-dependent differences in cell death rates during this process, which are validated by histopathology. The next tier of this approach quantifies the dynamics of micro-vasculature remodeling during growth after partial hepatectomy. Sinusoidal networks are shown to maintain contact with hepatocellular surfaces throughout the time course while bile networks are temporarily deconstructed only to return to baseline after more than a month. This work relates these tissue dynamics to tissue gene expression, showing complex synchronicity between morphological remodeling and transcriptional adaptations. Lastly, hepatocyte-specific adaptations to chronic ethanol intake and partial hepatectomy are interrogated by transcriptomic analysis to challenge the assumption that metabolic and proliferative activity induced by liver resection are performed by separate populations of cells. The disruption of gene and protein expression in two regulators of the glycolysis/gluconeogenesis pathways, Pfkfb1 and Pkm, suggest metabolic adaptions after PHx are guided by heterogeneity in the liver lobule (liver zonation), and not by the expression of proliferative marker Ki67. Together, these results give a sense of the many coinciding phenomena that are produced after major liver resection, with respect to sex- and disease-dependent dynamics. The sum of conclusions in this work demonstrates the value of an integrative cross-scale and multi-modal approach to systems biology related questions, enhancing the academic and clinical understanding of liver regeneration.
Subject Area
Systematic biology|Biochemistry|Molecular biology
Recommended Citation
Barnhart, Benjamin, "Partial Hepatectomy as a Model of Liver Regeneration: Network-Based Profiles" (2022). ProQuest ETD Collection - Thomas Jefferson University. AAI29258472.
https://jdc.jefferson.edu/dissertations/AAI29258472
