A computational model of liver tissue damage and repair.

Priyom Adhyapok,Sherry G Clendenon,James E Klaunig,Kenneth Dunn,James A Glazier,James P Sluka,Zemin Wang,Xiao Fu,Victoria D Sluka,Jordi Garcia-Ojalvo

doi:10.1371/journal.pone.0243451

Abstract

Drug induced liver injury (DILI) and cell death can result from oxidative stress in hepatocytes. An initial pattern of centrilobular damage in the APAP model of DILI is amplified by communication from stressed cells and immune system activation. While hepatocyte proliferation counters cell loss, high doses are still lethal to the tissue. To understand the progression of disease from the initial damage to tissue recovery or death, we computationally model the competing biological processes of hepatocyte proliferation, necrosis and injury propagation. We parametrize timescales of proliferation (α), conversion of healthy to stressed cells (β) and further sensitization of stressed cells towards necrotic pathways (γ) and model them on a Cellular Automaton (CA) based grid of lattice sites. 1D simulations show that a small α/β (fast proliferation), combined with a large γ/β (slow death) have the lowest probabilities of tissue survival. At large α/β, tissue fate can be described by a critical γ/β* ratio alone; this value is dependent on the initial amount of damage and proportional to the tissue size N. Additionally, the 1D model predicts a minimum healthy population size below which damage is irreversible. Finally, we compare 1D and 2D phase spaces and discuss outcomes of bistability where either survival or death is possible, and of coexistence where simulated tissue never completely recovers or dies but persists as a mixture of healthy, stressed and necrotic cells. In conclusion, our model sheds light on the evolution of tissue damage or recovery and predicts potential for divergent fates given different rates of proliferation, necrosis, and injury propagation.

Highlights

The liver performs a variety of essential functions including the clearance and metabolism of toxins in the bloodstream
The sterile inflammatory response is necessary to remove cellular debris and activate liver regeneration, this response has the potential to aggravate the injury. These observations raise the question; what tips the balance where the same set of cell behaviors that are needed for tissue repair and survival can, in some cases, lead to widespread cell death and irreparable tissue damage? To develop an understanding of the progression of liver damage in this system we have developed a Cellular Automata (CA) model of hepatocyte injury propagation, death and proliferation using a one dimensional (1D) linear chain and two dimensional (2D) hexagonal grids of simulated hepatocytes with key parameters associated to the timescales of these three processes
In this paper we have explored a Cellular Automaton (CA) based model of hepatocyte behavior in the liver following a drug induced centrilobular injury

Summary

Introduction

The liver performs a variety of essential functions including the clearance and metabolism of toxins in the bloodstream. To develop an understanding of the progression of liver damage in this system we have developed a Cellular Automata (CA) model of hepatocyte injury propagation, death and proliferation using a one dimensional (1D) linear chain and two dimensional (2D) hexagonal grids of simulated hepatocytes with key parameters associated to the timescales of these three processes. Our model has three different timescales — (A) α, associated with the cell proliferation timescale, (B) β, associated with the conversion of a healthy cell to a stressed cell, and (C) γ, associated with the process of the stressed cell dying Varying these parameters allows us to observe the phase space of outcomes leading to either tissue recovery or complete tissue death.

Results

Discussion

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Methods