An integrative computational model for intestinal tissue renewal

Abstract

Objectives : The luminal surface of the gut is lined with a monolayer of epithelial cells that acts as a nutrient absorptive engine and protective barrier. To maintain its integrity and functionality, the epithelium is renewed every few days. Theoretical models are powerful tools that can be used to test hypotheses concerning the regulation of this renewal process, to investigate how its dysfunction can lead to loss of homeostasis and neoplasia, and to identify potential therapeutic interventions. Here we propose a new multiscale model for crypt dynamics that links phenomena occurring at the subcellular, cellular and tissue levels of organisation. Methods : At the subcellular level, deterministic models characterise molecular networks, such as cell-cycle control and Wnt signalling. The output of these models determines the behaviour of each epithelial cell in response to intra-, inter-and extracellular cues. The modular nature of the model enables us to easily modify individual assumptions and analyse their effects on the system as a whole. Results : We perform virtual microdissection and labelling-index experiments, evaluate the impact of various model extensions, obtain new insight into clonal expansion in the crypt, and compare our predictions with recent mitochondrial DNA mutation data. Conclusions : We demonstrate that relaxing the assumption that stem-cell positions are fixed enables clonal expansion and niche succession to occur. We also predict that the presence of extracellular factors near the base of the crypt alone suffices to explain the observed spatial variation in nuclear beta-catenin levels along the crypt axis.

Cooperation among cancer cells as public goods games on Voronoi networks

“…Voronoi tesselations have been used [Rejniak & Anderson 2011, Csikász-Nagy et al 2013] to simulate the growth of multicellular spheroids [Schaller & Meyer-Hermann 2005, Beyer & MeyerHermann 2009 and the development of colorectal tumors [Meineke et al 2001, Van Leeuwen et al 2009], but not in the study of cooperation between cancer cells, or, more in general, in evolutionary game theory. A preliminary analysis of cooperation on Voronoi networks with a fixed diffusion range has been included in a recent experimental study of IGF-II production in pancreatic cancer [Archetti et al 2015].…”

Parameter-free methods distinguish Wnt pathway models and guide design of experiments

“…Despite many molecular advances, the pathway dynamics are still not well understood. Theoretical investigations of the Wnt/β-catenin pathway serve as testbeds for working hypotheses (5)(6)(7)(8)(9)(10)(11)(12).…”

Chaste: A test-driven approach to software development for biological modelling

“…Here the crypt bottom (missing from the cylindrical approximation) is projected from a 2D planar model onto the surface of a paraboloid that resembles a colonic crypt. In this approximation, the spring-spring interactions and the Delaunay triangulation are adjusted to accurately measure distance in the metric space of the paraboloid [15].…”

“…In this paper we concentrate on the model of intestinal crypts. Chaste has already been used to explore novel science in cancer modelling such as the Wnt signalling pathway's role in cell proliferation in the crypts [15].…”