Paracrine and autocrine regulation of gene expression by Wnt-inhibitor Dickkopf in wild-type and mutant hepatocytes

Niklas Hartung,Uwe Benary,Jana Wolf,Bente Kofahl

doi:10.1186/s12918-017-0470-9

Abstract

BackgroundCells are able to communicate and coordinate their function within tissues via secreted factors. Aberrant secretion by cancer cells can modulate this intercellular communication, in particular in highly organised tissues such as the liver. Hepatocytes, the major cell type of the liver, secrete Dickkopf (Dkk), which inhibits Wnt/ β-catenin signalling in an autocrine and paracrine manner. Consequently, Dkk modulates the expression of Wnt/ β-catenin target genes. We present a mathematical model that describes the autocrine and paracrine regulation of hepatic gene expression by Dkk under wild-type conditions as well as in the presence of mutant cells.ResultsOur spatial model describes the competition of Dkk and Wnt at receptor level, intra-cellular Wnt/ β-catenin signalling, and the regulation of target gene expression for 21 individual hepatocytes. Autocrine and paracrine regulation is mediated through a feedback mechanism via Dkk and Dkk diffusion along the porto-central axis. Along this axis an APC concentration gradient is modelled as experimentally detected in liver. Simulations of mutant cells demonstrate that already a single mutant cell increases overall Dkk concentration. The influence of the mutant cell on gene expression of surrounding wild-type hepatocytes is limited in magnitude and restricted to hepatocytes in close proximity. To explore the underlying molecular mechanisms, we perform a comprehensive analysis of the model parameters such as diffusion coefficient, mutation strength and feedback strength.ConclusionsOur simulations show that Dkk concentration is elevated in the presence of a mutant cell. However, the impact of these elevated Dkk levels on wild-type hepatocytes is confined in space and magnitude. The combination of inter- and intracellular processes, such as Dkk feedback, diffusion and Wnt/ β-catenin signal transduction, allow wild-type hepatocytes to largely maintain their gene expression.

Highlights

Cells are able to communicate and coordinate their function within tissues via secreted factors
Spatial model of hepatic Wnt signalling considering Dkk feedback and diffusion Structure and components of the model We aim to investigate the impact of Dkk on target gene expression in the context of an adenomatous polyposis coli (APC) gradient in the liver
We focus our modelling approach on the 15-25 hepatocytes that typically align along the porto-central axis parallel to a liver sinusoid (Fig. 1a) [6]

Summary

Introduction

Cells are able to communicate and coordinate their function within tissues via secreted factors. Glycolysis and glutamine synthesis occur predominantly in the PC region, while gluconeogenesis and urea formation occur predominantly in the PP region [2, 3, 5, 7, 8] This physiological phenomenon is referred to as functional zonation and is paralleled by distinct gene expression programmes [1,2,3,4,5,6,7]. According to current hypotheses extracellular factors, such as oxygen, hormones, or morphogens, are differently abundant along the porto-central axis and control the particular gene expression of hepatocytes located in specific zones of the liver sinusoids [7, 8]

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