Cell proliferation drives neural crest cell invasion of the intestine

Abstract

A general mathematical model of cell invasion is developed and validated with an experimental system. The model incorporates two basic cell functions: non-directed (diffusive) motility and proliferation to a carrying capacity limit. The model is used here to investigate cell proliferation and motility differences along the axis of an invasion wave. Mathematical simulations yield surprising and counterintuitive predictions. In this general scenario, cells at the invasive front are proliferative and migrate into previously unoccupied tissues while those behind the front are essentially nonproliferative and do not directly migrate into unoccupied tissues. These differences are not innate to the cells, but are a function of proximity to uninvaded tissue. Therefore, proliferation at the invading front is the critical mechanism driving apparently directed invasion. An appropriate system to experimentally validate these predictions is the directional invasion and colonization of the gut by vagal neural crest cells that establish the enteric nervous system. An assay using gut organ culture with chick-quail grafting is used for this purpose. The experimental results are entirely concordant with the mathematical predictions. We conclude that proliferation at the wavefront is a key mechanism driving the invasive process. This has important implications not just for the neural crest, but for other invasion systems such as epidermal wound healing, carcinoma invasion and other developmental cell migrations.

Spatial Analysis of Multi-species Exclusion Processes: Application to Neural Crest Cell Migration in the Embryonic Gut

“…Past modeling of the colonization of the ENS has demonstrated the importance of ENC cell proliferation in comparison with the motility (Simpson et al 2007b;Zhang et al 2010). Our analysis here strongly suggests that the appearance of labeled ENC patches may be caused by dominance of ENC proliferation to other mechanisms, reinforcing previous conclusions.…”

“…To gain a better understanding of the basis for variability of these ENC cell spatial distributions (labeled and unlabeled), we use a cellular automata (CA) model to investigate the effect of four key mechanisms in the developing ENC cell migration process (Binder et al 2008;Binder and Landman 2009;Simpson et al 2007aSimpson et al , 2007bZhang et al 2010). The mechanisms comprise of ENC cell motility, ENC cell proliferation, the initial number or density of ENC cells that are labeled at the start of the migration and the underlying gut tissue growth.…”

The migratory behavior of immature enteric neurons

“…It is implicit in this argument that enteric neuronal differentiation directly inhibits migration, or indirectly inhibits migration by reducing proliferation; proliferation has recently been shown to be essential for migration (Simpson et al, 2007). Our studies have shown that the differentiation of ENCCs into neurons does not result in the immediate termination of migration, as around 50% of the immature neurons were observed to migrate.…”

“…If neuronal differentiation retards the migration of ENCCs directly, endothelin-3 might promote ENCC migration by inhibiting differentiation. As proliferation is essential for ENCC migration (Simpson et al, 2007), endothelin-3 might promote ENCC migration indirectly by increasing the rate of proliferation (Hearn et al, 1998;Bondurand et al, 2006;Nagy and Goldstein, 2006). It is therefore of interest to determine whether immature neurons migrate, and if so, whether they migrate at the same speed as undifferentiated ENCCs.…”

Fractional models for the migration of biological cells in complex spatial domains

“…In vitro assays agree with the constant wavespeed assumption [2,12], but in vivo measurements of the invasion speed of the enteric neural crest cell population are often not so straightforward. For example, the wave front is not always clearly defined, and its position may vary substantially in different experiments.…”