Homeostasis, injury and recovery dynamics at multiple scales in a self-organizing mouse intestinal crypt
- AstraZeneca, United Kingdom
- University of Liverpool, United Kingdom
- Janssen, Belgium
- Quadram Institute, United Kingdom
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.
Data availability
The current manuscript is a computational study. No data have been generated for this manuscript. Modelling code is uploaded as Source Code.zip file
Article and author information
Author details
David Mark Pritchard
Funding
European Federation of Pharmaceutical Industries and Associations (Innovative Medicines Initiative 2,No. 116030)
- Louis Gall
- Carrie Duckworth
- Ferran Jardi
- Lieve Lammens
- David Mark Pritchard
- Carmen Pin
Horizon 2020 Framework Programme (Innovative Medicines Initiative 2,No. 116030)
- Louis Gall
- Carrie Duckworth
- Ferran Jardi
- Lieve Lammens
- David Mark Pritchard
- Carmen Pin
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experiments were performed in an Association for Assessment and Accreditation of Laboratory Animal Care approved rodent facility and in accordance with the applicable animal welfare guidelines and legislation. Experimental procedures were approved by the institutional ethics committee. Ten-week-old male C57/BL6Y mice were obtained from Charles River (France). Mice were housed in polysulfon cages with corncob bedding under standard conditions of room temperature (21{degree sign}C {plus minus} 2), relative humidity (55% {plus minus} 15) and a 12-h light cycle. Water and a certified rodent pelleted maintenance diet were supplied ad libitum. Nest material and rodent retreats were provided for environmental enrichment.
Copyright
© 2023, Gall et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Homeostasis, injury and recovery dynamics at multiple scales in a self-organizing mouse intestinal crypt
eLife 12:e85478.
https://doi.org/10.7554/eLife.85478
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