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

Abstract

We have built a multi-scale agent-based model (ABM) that reproduces the self-organizing behaviour reported for the intestinal crypt. We demonstrate that a stable spatial organization emerges from the dynamic interaction of multiple signalling pathways, such as Wnt, Notch, BMP, RNF43/ZNRF3 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 disturbs 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. 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 discovery.

A dynamic model of the intestinal epithelium integrates multiple sources of preclinical data and enables clinical translation of drug‐induced toxicity

“…The impact of cross‐species differences on toxicity responses may be circumvented by the adoption of human‐derived intestinal organoids and microphysiological systems, which are being integrated into drug safety assessment strategies at a fast pace. Likewise, highly mechanistic models, such as the recently developed agent‐based model of the intestinal crypt, 53 comprising species specific differences in physiology could provide accurate clinical predictions at early stages of the drug development pipeline.…”