Homeostasis, injury, and recovery dynamics at multiple scales in a self-organizing mouse intestinal crypt

Abstract

The maintenance of the functional integrity of the intestinal epithelium requires a tight coordination between cell production, migration, and shedding along the crypt–villus axis. Dysregulation of these processes may result in loss of the intestinal barrier and disease. With the aim of generating a more complete and integrated understanding of how the epithelium maintains homeostasis and recovers after injury, we have built a multi-scale agent-based model (ABM) of the mouse intestinal epithelium. We demonstrate that stable, self-organizing behaviour in the crypt emerges from the dynamic interaction of multiple signalling pathways, such as Wnt, Notch, BMP, ZNRF3/RNF43, and YAP-Hippo pathways, which regulate proliferation and differentiation, respond to environmental mechanical cues, form feedback mechanisms, and modulate the dynamics of the cell cycle protein network. The model recapitulates the crypt phenotype reported after persistent stem cell ablation and after the inhibition of the CDK1 cycle protein. Moreover, we simulated 5-fluorouracil (5-FU)-induced toxicity at multiple scales starting from DNA and RNA damage, which disrupts the cell cycle, cell signalling, proliferation, differentiation, and migration and leads to loss of barrier integrity. During recovery, our in silico crypt regenerates its structure in a self-organizing, dynamic fashion driven by dedifferentiation and enhanced by negative feedback loops. Thus, the model enables the simulation of xenobiotic-, in particular chemotherapy-, induced mechanisms of intestinal toxicity and epithelial recovery. Overall, we present a systems model able to simulate the disruption of molecular events and its impact across multiple levels of epithelial organization and demonstrate its application to epithelial research and drug development.

Keywords

• systems models
• intestinal crypt
• drug toxicity
• agent-based model
• stem cells
• 5-FU