Model predicts fundamental role of biomechanical control of cell cycle progression during liver regeneration after partial hepatectomy

TL;DR

This study introduces a computational model of liver regeneration that emphasizes biomechanical control of cell cycle progression, successfully replicating experimental data and predicting species-specific proliferation patterns.

Contribution

The paper presents a novel simulation model incorporating biomechanical growth control, advancing understanding of liver regeneration mechanisms after partial hepatectomy.

Findings

Model reproduces experimental regeneration patterns

Biomechanical control minimizes neighboring proliferating cells

Predicts species-specific proliferation patterns

Abstract

Partial hepatectomy (PHx) is a surgical intervention where a part of the liver is removed. Due to its extraordinary capacity to regenerate, the liver is able to regenerate about two-thirds of its mass within a few weeks. Nevertheless, in some patients regeneration fails. Understanding the principles and limitations underlying regeneration may permit to control this process and prospectively improve the regeneration. Here, we established a simulation model to mimic the process of regeneration in the liver lobe of a mouse. This model represents each hepatocyte individually and builds upon a previous computational model of regeneration of drug induced damage in a single liver lobule. The present study simulates entire liver lobes that consist of hundreds to thousands of lobules. It accounts for biomechanical control of cell cycle progression (Biomechanical Growth Control), which has not been considered in that previous work. The model reproduced the available experimental observations only if BGC was taken into account. Interestingly, the model predicted that BGC minimizes the number of proliferating neighbor cells of a proliferating cell resulting in a checkerboard-like proliferation pattern. Moreover, the model predicted different cell proliferation patterns in pigs and mice that corresponded to data obtained from regenerating tissue of the two species. In conclusion, the here established model suggest that biomechanical control mechanisms may play a significant role in liver regeneration after PHx.