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) Nature 459, 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 Biol 7, 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.
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany.
Peter
P
Buske
Jens
J
Przybilla
Markus
M
Loeffler
Norman
N
Sachs
Toshiro
T
Sato
Hans
H
Clevers
Joerg
J
Galle
D001696:Biomechanical Phenomena; D002452:Cell Count; D002454:Cell Differentiation; D049109:Cell Proliferation; D003198:Computer Simulation; D004847:Epithelial Cells / Q000502:physiology; D007422:Intestines / Q000166:cytology*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D008954:Models, Biological; D009940:Organoids / Q000378:metabolism*; D019879:Paneth Cells / Q000502:physiology; D055153:Stem Cell Niche; D013234:Stem Cells / Q000166:cytology