Computational Models Reveal a Passive Mechanism for Cell Migration in the Crypt

Abstract

Cell migration in the intestinal crypt is essential for the regular renewal of the epithelium, and the continued upward movement of cells is a key characteristic of healthy crypt dynamics. However, the driving force behind this migration is unknown. Possibilities include mitotic pressure, active movement driven by motility cues, or negative pressure arising from cell loss at the crypt collar. It is possible that a combination of factors together coordinate migration. Here, three different computational models are used to provide insight into the mechanisms that underpin cell movement in the crypt, by examining the consequence of eliminating cell division on cell movement. Computational simulations agree with existing experimental results, confirming that migration can continue in the absence of mitosis. Importantly, however, simulations allow us to infer mechanisms that are sufficient to generate cell movement, which is not possible through experimental observation alone. The results produced by the three models agree and suggest that cell loss due to apoptosis and extrusion at the crypt collar relieves cell compression below, allowing cells to expand and move upwards. This finding suggests that future experiments should focus on the role of apoptosis and cell extrusion in controlling cell migration in the crypt.

Cell proliferation within small intestinal crypts is the principal driving force for cell migration on villi

“…Passive mitotic pressure generated by cell division in the intestinal crypts, and subsequent gradual expansion in cell diameter along the crypt–villus axis, provides a plausible explanation for the steady continuous migration of epithelial cells (3, 4). Indeed, previous computational models suggest that these forces alone are sufficient to explain observed rates of cell migration, at least within the crypt (5–10). Conversely, other studies have reported continued epithelial cell migration or evidence for villus-to-crypt feedback in regulating proliferation rates when crypts were targeted with irradiation, ischemia, or cytotoxic agents (11–18).…”

Simulating tissue mechanics with agent-based models: concepts, perspectives and some novel results

“…Macklin et al [155] have addressed ductile carcinoma's. A number of researcher has also been focused on intestinal crypts and epithelial tissues, studying e.g., cell organization and the role of basement membranes, and predicting the behavior of the tissue during steady state as well as after cell damage [35,37,52,[156][157][158][159][160][161][162][163].…”

Host‐microbe interaction in the gastrointestinal tract

“…In the intestine, stochastic modelling of monoclonal expansion of stem cells, together with Cre/LoxP-based and other lineage tracing experimental strategies, have been instrumental in demonstrating that small intestinal epithelial stem cells are equipotent regarding their ability to occupy with their descendants the entire gland, divide symmetrically and be replaced at random according to a neutral drift pattern (Lopez-Garcia et al, 2010;Snippert et al, 2010;Leushacke et al, 2016). Among computational models, individual-based models have been widely used to describe the spatio-temporal dynamics of single cells, biomechanical properties, cell-cell and cell-matrix interactions, cell density effects and signalling pathways within the crypts (Pitt-Francis et al, 2009;Fletcher et al, 2012;Dunn et al, 2013;Pin et al, 2015). Both analytical and computational models of the epithelium are suitable for extensions, in alignment with data gathering, to account for interactions with the microbiome, immune system and enteric nervous system.…”