Elucidating the Mechanisms of Dynamic and Robust Control of the Liver Homeostatic Renewal Process: Cell Network Modeling and Analysis

Abstract

Recent experimental investigations of liver homeostatic renewal have identified high replication capacity hepatocyte populations as the primary maintainers of liver mass. However, the molecular and cellular processes controlling liver homeostatic renewal remain unknown. To address this problem, we developed and analyzed a mathematical model describing cellular network interactions underlying liver homeostatic renewal. Model simulation results demonstrate that without feedback control, basic homeostatic renewal is not robust to disruptions, leading to tissue loss under persistent/repetitive insults. Consequently, we extended our basic model to incorporate putative regulatory interactions and investigated how such interactions may confer robustness on the homeostatic renewal process. We utilized a Design of Experiments approach to identify the combination of feedback interactions that yields a cell network model of homeostatic renewal capable of maintaining liver mass robustly during persistent/repetitive injury. Simulations of this robust model indicate that repeated injury destabilizes liver homeostasis within several months, which differs from epidemiological observations of a much slower decay of liver function occurring over several years. To address this discrepancy, we extended the model to include feedback control by liver nonparenchymal cells. Simulations and analysis of the final multicellular feedback control network suggest that achieving robust liver homeostatic renewal requires intrinsic stability in a hepatocellular network combined with feedback control by nonparenchymal cells.

Editorial for the Festschrift Honoring the Legacy of Babatunde A. Ogunnaike (1956–2022)

“…17 Biological and biomedical applications are covered in the papers of Navarathna et al, who discuss pressure-induced faults in glucose monitors, 18 Christie et al, who present a model-based approach for diagnosing hypercalcemia, 19 and Cook et al, who describe the mechanisms of control of the liver homeostatic renewal process via cell network modeling and analysis. 20 Birtwistle also employs dynamic modeling, focusing on modeling eukaryotic DNA synthesis. 21 The Festschrift also includes several contributions that focus on materials science and engineering, such as the paper of Zhu et al, who report on the preparation of high-strength SBR vitrimers, 22 Isfahani et al, reviewing the use of two-dimensional materials (such as MXenes) for membrane gas separations, 23 and Schork, who provides a perspective on the commercialization of microemulsion technology.…”

“…Biological and biomedical applications are covered in the papers of Navarathna et al, who discuss pressure-induced faults in glucose monitors, Christie et al, who present a model-based approach for diagnosing hypercalcemia, and Cook et al, who describe the mechanisms of control of the liver homeostatic renewal process via cell network modeling and analysis . Birtwistle also employs dynamic modeling, focusing on modeling eukaryotic DNA synthesis …”