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.
Highlights
The epithelium of the small intestine is one of the most rapidly regenerating tissues with a turnover time of only a few days
Our study demonstrates that 3D computational tissue models can support a mechanistic understanding of long-term tissue dynamics under homeostasis and during transformation
This permanent regeneration is enabled by intestinal stem cells (SCs) that reside at the bottom of small invaginations of the tissue, the intestinal crypts
Summary
The epithelium of the small intestine is one of the most rapidly regenerating tissues with a turnover time of only a few days This permanent regeneration is enabled by intestinal stem cells (SCs) that reside at the bottom of small invaginations of the tissue, the intestinal crypts. The vast majority of these SC descendants are enterocytes (ECs) and two types of secretory cells, Paneth (PCs) and goblet cells (GCs). Their specification is largely controlled by Wntand Notch signalling (reviewed in [5]). These cells, while differentiating, move out of the crypt onto the villi, finger-like protrusions of the tissue, where they become shed. The clones of all SCs compete for occupying this niche
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