On the biomechanics of stem cell niche formation in the gut - Modelling growing organoids

Peter Buske, Jens Przybilla, Markus Loeffler, Norman Sachs, Toshiro Sato, Hans Clevers, Joerg Galle

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3475-3487
Number of pages13
JournalFEBS Journal
Volume279
Issue number18
DOIs
Publication statusPublished - 2012 Sep 1

Keywords

  • computer model
  • crypt formation
  • intestinal tissue culture
  • mechanobiology
  • stem cell niche

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Buske, P., Przybilla, J., Loeffler, M., Sachs, N., Sato, T., Clevers, H., & Galle, J. (2012). On the biomechanics of stem cell niche formation in the gut - Modelling growing organoids. FEBS Journal, 279(18), 3475-3487. https://doi.org/10.1111/j.1742-4658.2012.08646.x