An integrative computational model for intestinal tissue renewal
I.M.M. van Leeuwen‚ G.R. Mirams‚ A. Walter‚ A. Fletcher‚ P. Murray‚ J. Osborne‚ S. Varma‚ S.J. Young‚ J. Cooper‚ B. Doyle‚ J. Pitt−Francis‚ L. Momtahan‚ P. Pathmanathan‚ J.P. Whiteley‚ S.J. Chapman‚ D.J. Gavaghan‚ O.E. Jensen‚ J.R. King‚ P.K. Maini‚ S.L. Waters and H.M. Byrne
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 the 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 extra-cellular cues. The modular nature of the model enables us to modify easily 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 mtDNA 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.