A Two-Dimensional Model of the Colonic Crypt Accounting for the Role of the Basement Membrane and Pericryptal Fibroblast Sheath

Abstract

The role of the basement membrane is vital in maintaining the integrity and structure of an epithelial layer, acting as both a mechanical support and forming the physical interface between epithelial cells and the surrounding connective tissue. The function of this membrane is explored here in the context of the epithelial monolayer that lines the colonic crypt, test-tube shaped invaginations that punctuate the lining of the intestine and coordinate a regular turnover of cells to replenish the epithelial layer every few days. To investigate the consequence of genetic mutations that perturb the system dynamics and can lead to colorectal cancer, it must be possible to track the emerging tissue level changes that arise in the crypt. To that end, a theoretical crypt model with a realistic, deformable geometry is required. A new discrete crypt model is presented, which focuses on the interaction between cell- and tissue-level behaviour, while incorporating key subcellular components. The model contains a novel description of the role of the surrounding tissue and musculature, based upon experimental observations of the tissue structure of the crypt, which are also reported. A two-dimensional (2D) cross-sectional geometry is considered, and the shape of the crypt is allowed to evolve and deform. Simulation results reveal how the shape of the crypt may contribute mechanically to the asymmetric division events typically associated with the stem cells at the base. The model predicts that epithelial cell migration may arise due to feedback between cell loss at the crypt collar and density-dependent cell division, an hypothesis which can be investigated in a wet lab. This work forms the basis for investigation of the deformation of the crypt structure that can occur due to proliferation of cells exhibiting mutant phenotypes, experiments that would not be possible in vivo or in vitro.

Author Summary

At the onset of colorectal carcinogenesis, marked changes can be observed in the structure and dynamics of the crypts of Lieberkühn. These test tube shaped glands regularly punctuate the surface of the gut and are lined with a monolayer of epithelial cells which divide and migrate upwards to renew the intestinal surface every few days. The process by which the crypt structures breakdown, and the compliant environment that can be subsequently provided to mutated cells to allow the formation of adenomatous growths, is not yet well characterised. A limiting factor in the understanding of this process is the ability to observe easily the initial changes that occur, and which are necessary to disrupt the normal behaviour of the system. However, a predictive, theoretical model of the crypt that mimics the geometry and the tissue architecture can be used to perform in silico experiments and further such understanding. A model is introduced here that addresses the tissue structure of the crypt, and the stability it provides to the epithelial layer, while remaining deformable and without imposing a fixed geometry.