On the biomechanics of stem cell niche formation in the gut – modelling growing organoids

In vitro culture of intestinal tissue has been attempted for decades. Only recently did Sato et al. [Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J., et al. (2009) Nature459, 262–265] succeed in establishing long‐term intestinal culture, demonstrating that cells expressing the Lgr5 gene can give rise to organoids with crypt‐like domains similar to those found in vivo. In these cultures, Paneth cells provide essential signals supporting stem cell function. We have recently developed an individual cell‐based computational model of the intestinal tissue [Buske, P., Galle, J., Barker, N., Aust, G., Clevers, H. & Loeffler, M. (2011) PLoS Comput Biol7, e1001045]. The model is capable of quantitatively reproducing a comprehensive set of experimental data on intestinal cell organization. Here, we present a significant extension of this model that allows simulation of intestinal organoid formation in silico. For this purpose, we introduce a flexible basal membrane that assigns a bending modulus to the organoid surface. This membrane may be re‐organized by cells attached to it depending on their differentiation status. Accordingly, the morphology of the epithelium is self‐organized. We hypothesize that local tissue curvature is a key regulatory factor in stem cell organization in the intestinal tissue by controlling Paneth cell specification. In simulation studies, our model closely resembles the spatio‐temporal organization of intestinal organoids. According to our results, proliferation‐induced shape fluctuations are sufficient to induce crypt‐like domains, and spontaneous tissue curvature induced by Paneth cells can control cell number ratios. Thus, stem cell expansion in an organoid depends sensitively on its biomechanics. We suggest a number of experiments that will enable new insights into mechano‐transduction in the intestine, and suggest model extensions in the field of gland formation.