title: Stem cell competition in the gut: insights from multi-scale computational modelling.
abstract: Three-dimensional (3D) computational tissue models can provide a comprehensive description of tissue dynamics at the molecular, cellular and tissue level. Moreover, they can support the development of hypotheses about cellular interactions and about synergies between major signalling pathways. We exemplify these capabilities by simulation of a 3D single-cell-based model of mouse small intestinal crypts. We analyse the impact of lineage specification, distribution and cellular lifespan on clonal competition and study effects of Notch- and Wnt activation on fixation of mutations within the tissue. Based on these results, we predict that experimentally observed synergistic effects between autonomous Notch- and Wnt signalling in triggering intestinal tumourigenesis originate in the suppression of Wnt-dependent secretory lineage specification by Notch, giving rise to an increased fixation probability of Wnt-activating mutations. Our study demonstrates that 3D computational tissue models can support a mechanistic understanding of long-term tissue dynamics under homeostasis and during transformation.
authors.affiliation: Interdisciplinary Center for Bioinformatics, Leipzig University, Haertelstr. 16-18, 04107 Leipzig, Germany.
authors.forename: Torsten
authors.identifier: 0000-0001-5489-7405
authors.initials: T
authors.lastname: Thalheim
authors.affiliation: Interdisciplinary Center for Bioinformatics, Leipzig University, Haertelstr. 16-18, 04107 Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Buske
authors.affiliation: Interdisciplinary Center for Bioinformatics, Leipzig University, Haertelstr. 16-18, 04107 Leipzig, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Przybilla
authors.affiliation: Interdisciplinary Center for Bioinformatics, Leipzig University, Haertelstr. 16-18, 04107 Leipzig, Germany.
authors.forename: Karen
authors.initials: K
authors.lastname: Rother
authors.affiliation: Interdisciplinary Center for Bioinformatics, Leipzig University, Haertelstr. 16-18, 04107 Leipzig, Germany Institute for Medical Informatics, Statistics and Epidemiology, Leipzig University, Haertelstr. 16-18, 04107 Leipzig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Loeffler
authors.affiliation: Interdisciplinary Center for Bioinformatics, Leipzig University, Haertelstr. 16-18, 04107 Leipzig, Germany galle@izbi.uni-leipzig.de.
authors.forename: Joerg
authors.identifier: 0000-0003-1161-3788
authors.initials: J
authors.lastname: Galle
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007422:Intestines / Q000473:pathology; D008954:Models, Biological; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D009363:Neoplasm Proteins; D051880:Receptors, Notch; D051153:Wnt Proteins
keywords: Paneth cell specification; Wnt and Notch signalling; clonal competition; mouse small intestine; three-dimensional computational model