Mathematical modeling of monoclonal conversion in the colonic crypt

Area of Science:

• Computational biology
• Gastroenterology
• Cell biology

Background:

• Colonic crypts are dynamic structures crucial for gut homeostasis.
• Understanding stem cell behavior is key to crypt regeneration and disease prevention.
• Monoclonal conversion, where one cell type dominates, is a significant process in crypt dynamics.

Purpose of the Study:

• To develop and utilize a novel spatial multiscale model of a colonic crypt.
• To investigate monoclonal conversion under two distinct hypotheses of stem cell behavior.
• To assess the impact of spatial structure on crypt repopulation dynamics.

Main Methods:

• Coupling cell cycle dynamics (including division) with cell mechanics in a spatial model.
• Simulating virtual experiments by introducing a labeled mutation into a single crypt cell.
• Tracking mutant clonal population growth over time under different stem cell hypotheses.
• Comparing model results with existing spatial and non-spatial population models.

Main Results:

• A stable crypt architecture naturally emerged under the hypothesis where cell proliferation is microenvironment-governed (symmetric division).
• The hypothesis of intrinsic stemness (asymmetric division) required population-dependent feedback for stability.
• Spatial crypt structure significantly influenced the timescale of monoclonal conversion.

Conclusions:

• The microenvironment plays a critical role in maintaining colonic crypt stability and architecture.
• Stem cell behavior and division symmetry are key determinants of crypt dynamics.
• Spatial modeling is essential for accurately predicting the temporal dynamics of crypt repopulation and monoclonal conversion.