A Comprehensive Model of the Spatio-Temporal Stem Cell and Tissue Organisation in the Intestinal Crypt

We introduce a novel dynamic model of stem cell and tissue organisation in murine intestinal crypts. Integrating the molecular, cellular and tissue level of description, this model links a broad spectrum of experimental observations encompassing spatially confined cell proliferation, directed cell migration, multiple cell lineage decisions and clonal competition.Using computational simulations we demonstrate that the model is capable of quantitatively describing and predicting the dynamic behaviour of the intestinal tissue during steady state as well as after cell damage and following selective gain or loss of gene function manipulations affecting Wnt- and Notch-signalling. Our simulation results suggest that reversibility and flexibility of cellular decisions are key elements of robust tissue organisation of the intestine. We predict that the tissue should be able to fully recover after complete elimination of cellular subpopulations including subpopulations deemed to be functional stem cells. This challenges current views of tissue stem cell organisation.Author Summary: In the murine small intestine there are more than a million organized groups of proliferating cells, the crypts, each of which contains about 250–300 cells. About 60% of these cells are in rapid cycle. The functional stem cells of this tissue have been demonstrated to reside at defined positions at the lower third of the crypt and to give rise to four different cell types. Considering this simple structure the murine intestine is an ideal system to study general aspects of tissue organization. Here, we introduce a comprehensive and predictive computer model of the spatio-temporal organization of the murine intestine which describes how cell production and cell fate decisions could be organized in steady state as well as under perturbations. The model is based on single cells acting as individual agents, updating their status within a certain set of options governed by some active rules and on signals received from the environment. This kind of self-organization enables effective tissue regeneration without assuming an explicit stem cell population that maintains itself by asymmetric division. Thus, the model offers a novel systems biological view on crypt stem cell and tissue organisation.