Scientific Publications
An individual based computational model of intestinal crypt fission and its application to predicting unrestrictive growth of the intestinal epithelium
Integrative Biology, 7, 213
Intestinal crypt fission is a homeostatic phenomenon, observable in healthy adult mucosa, but which also plays a pathological role as the main mode of growth of some intestinal polyps. Building on our previous individual based model for the small intestinal crypt and on in vitro cultured intestinal organoids, we modelled crypt fission as a budding process based on fluid mechanics at the individual cell level and extrapolated predictions for growth of the intestinal epithelium. Budding was observed in regions of organoids with abundant Paneth cells. By testing several hypotheses, we found that when Paneth cells were more resistant to deformation than stem cells, a hypothesis that was supported by AFM measurements of single cells, buds were biomechanically initiated mainly by single stem cells surrounded by Paneth cells. The time intervals between consecutive budding events observed in vitro and simulated by the model were 2.62 and 2.84 days, respectively. Predicted cell dynamics was unaffected within the original crypt which retained full capacity to provide cells to the epithelium throughout fission. The mitotic pressure in simulated primary crypts forced upward migration of buds, which simultaneously grew into new protruding crypts. Growth and migration of these secondary crypts were unrelated events. The crypt growth rate was 0.99 days-1 in organoids and 1.03 days-1 in simulations. Our model predicts that the new crypt reaches its final size in 4.6 days and requires 6.2 days to migrate to the top in primary crypt. Assuming unrestricted crypt fission and multiple budding events, a maximal growth rate of the intestinal epithelium of 0.10 days-1 is predicted. Approximately 22 days are required for a 10-fold increase of polyp size. These predictions are in agreement with the time reported to develop macroscopic adenomas in mice after loss of Apc in intestinal stem cells.
Integrative Biology, 7, 213
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