Cell migration in gut homeostasis – HOMEOGUT

The epithelium of the small intestine is composed of a single layer of cells that line the villi that project into the lumen of the gut, and the crypts that descend into the underlying connective tissue. Dividing stem cells are contained within the crypts and they give rise to five types of specialized epithelial cells. Most of those cells travel upwards from the stem cell compartment towards the villus tip where they die by anoikis and are shed into the lumen. However, the mechanism responsible for the migration of intestinal cells remains largely unknown.

The basal surface of single-layer epithelium is underlined by the basement membrane (BM), a thin and dense sheet-like structure that is produced by coordinated actions of epithelial cells and stromal fibroblasts. The BM provides structural support for the epithelium, promotes cell adhesions, maintains cell polarity and has a role in compartmentalization of the tissue by separating epithelium from the stroma.

The major components of the stroma are fibroblasts, myofibroblasts, immune cells, blood vessels and the network of extracellular matrix (ECM) mostly made of collagen I fibers. Fibroblasts and myofibroblasts play a role in gut homeostasis by producing growth factors, cytokines and ECM proteins. Whether fibroblasts and basement membrane play an active role in epithelial cell migration during gut homeostasis is unknown.

The intestine is one of the most proliferative tissues in the body. The entire intestinal epithelium is renewed every week thus, if not controlled, homeostasis has a high probability to fail. Uncoupling cell proliferation from apoptosis and possibly from cell migration can lead to pathologies such as tumor formation.

Using complementary model systems such as: transgenic mice, ex vivo intestinal slices, reconstituted gut on the chip and computer simulations, we propose to unravel the fundamental mechanisms of cell migration during intestinal homeostasis. In particular, we will address the following questions:
Do epithelial cells migrate actively using cellular protrusions or passively, being pushed by dividing cells?
Are epithelial cells transported by underlying fibroblasts or basement membrane flow?
Do geometry, stiffness and organization of the ECM control the balance between cell proliferation and migration?