期刊
JOURNAL OF THE ROYAL SOCIETY INTERFACE
卷 13, 期 121, 页码 -出版社
ROYAL SOC
DOI: 10.1098/rsif.2016.0218
关键词
mouse small intestine; clonal competition; Paneth cell specification; Wnt and Notch signalling; three-dimensional computational model
资金
- Bundesministerium fur Bildung and Forschung [0316065A, 031A312]
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.
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