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

Abstract

The functional integrity of the intestinal epithelial barrier relies on tight coordination of cell proliferation and migration, with failure to regulate these processes resulting in disease. It is not known whether cell proliferation is sufficient to drive epithelial cell migration during homoeostatic turnover of the epithelium. Nor is it known precisely how villus cell migration is affected when proliferation is perturbed. Some reports suggest that proliferation and migration may not be related while other studies support a direct relationship. We used established cell-tracking methods based on thymine analog cell labeling and developed tailored mathematical models to quantify cell proliferation and migration under normal conditions and when proliferation is reduced and when it is temporarily halted. We found that epithelial cell migration velocities along the villi are coupled to cell proliferation rates within the crypts in all conditions. Furthermore, halting and resuming proliferation results in the synchronized response of cell migration on the villi. We conclude that cell proliferation within the crypt is the primary force that drives cell migration along the villus. This methodology can be applied to interrogate intestinal epithelial dynamics and characterize situations in which processes involved in cell turnover become uncoupled, including pharmacological treatments and disease models.—Parker, A., Maclaren, O. J., Fletcher, A. G., Muraro, D., Kreuzaler, P. A., Byrne, H. M., Maini, P. K., Watson, A. J. M., Pin, C. Cell proliferation within small intestinal crypts is the principal driving force for cell migration on villi.

Loss of N‐WASP drives early progression in an Apc model of intestinal tumourigenesis

“…Loss of N‐WASP resulted in a slight increase in the number of Paneth and goblet cells and further displacement of their position along the crypt‐villus axis than that caused by Apc loss alone. Loss of N‐WASP also increased the distance that cells migrated up along the crypt–villus axis over 24 h. Migration up the crypt–villus axis is thought to be driven mainly by proliferation , so this result was surprising as loss of N‐WASP did not alter proliferation. Previous studies found differential expression of integrins and matrix components in crypt–villus regions, which might impact on migration through differential adhesion .…”

The integrity of the FOG‐2 LXCXE pRb‐binding motif is required for small intestine homeostasis

“…The mouse small intestine is an interesting model for in vivo studies of the regulation of cell growth and differentiation. The higher levels of cell proliferation observed in the intestinal crypts are associated with crypt cell migration (Parker et al., ). Stem‐cell mitosis within the crypts generates transit cells, which divide to generate the villus enterocytes.…”

Gamma‐H2AX immunofluorescence for the detection of tissue‐specific genotoxicity in vivo

“…The stem cells at the base of intestinal crypts are continuously proliferating to regenerate the intestinal mucosal epithelium. They differentiate into multiple functionally distinct epithelial subtypes, which then migrate upward to the villus tips (Parker et al, ). It has been shown that gamma‐H2AX foci exist in parallel to replication fork breakage in the S phase, which indicates the presence of gamma‐H2AX positivity in dividing cells (An et al, ).…”