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Stem cell competition in the gut: insights from multi-scale computational modelling.

Torsten Thalheim1, Peter Buske1, Jens Przybilla1

  • 1Interdisciplinary Center for Bioinformatics, Leipzig University, Haertelstr. 16-18, 04107 Leipzig, Germany.

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|August 19, 2016
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Summary

Three-dimensional computational tissue models reveal how cellular dynamics and signaling pathways influence intestinal tissue. These models predict that Notch signaling suppresses Wnt-driven secretory cell development, increasing tumor-causing mutation fixation.

Keywords:
Paneth cell specificationWnt and Notch signallingclonal competitionmouse small intestinethree-dimensional computational model

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Area of Science:

  • Computational biology
  • Systems biology
  • Tissue engineering

Background:

  • Three-dimensional (3D) computational tissue models offer detailed insights into molecular, cellular, and tissue-level dynamics.
  • These models facilitate hypothesis generation regarding cellular interactions and signaling pathway synergies.

Purpose of the Study:

  • To simulate a 3D single-cell-based model of mouse small intestinal crypts.
  • To analyze the impact of lineage specification, distribution, and cellular lifespan on clonal competition.
  • To investigate the effects of Notch and Wnt pathway activation on mutation fixation within the tissue.

Main Methods:

  • Development and simulation of a 3D single-cell-based computational model.
  • Analysis of lineage specification, cellular distribution, and lifespan effects on clonal dynamics.
  • Modeling of Notch and Wnt signaling pathway activation and their influence on mutation fixation.

Main Results:

  • Simulations revealed the impact of lineage specification, distribution, and lifespan on clonal competition in intestinal crypts.
  • Notch and Wnt pathway activation were studied for their effects on mutation fixation.
  • A prediction was made regarding the synergistic effects of Notch and Wnt signaling in intestinal tumorigenesis.

Conclusions:

  • 3D computational tissue models can mechanistically explain long-term tissue dynamics during homeostasis and transformation.
  • The study predicts that Notch signaling suppresses Wnt-dependent secretory lineage specification, enhancing Wnt-activating mutation fixation.
  • This mechanism explains observed synergistic effects of Notch and Wnt signaling in intestinal tumorigenesis.