Epithelial cell migration in gut homeostasis

The gut epithelium acts as a barrier between the outside world and the body while at the same time ensuring nutrient absorption. The small intestine epithelium is composed of a single layer of columnar cells that line the villi that project into the gut's lumen and the crypts that descend into the connective tissue. The constant epithelium renewal is achieved by stem cell proliferation in the crypts giving rise to specialized epithelial cell types. Upon exiting the crypt, most cell types migrate towards the villus tip, where they die and are shed into the lumen. The basal surface of the epithelium is underlined by the basement membrane (BM), a thin and dense sheet-like structure composed of a network of collagen IV and laminin on which cells adhere and migrate. It was believed that cell migration on the BM is a passive process, driven by mitotic pressure generated at the crypts. However, recently we showed that mitotic pressure has a short-range effect restricted to the crypts and that active migration is required to reach the villus tip (Krndija et al., Science, 2019). While cells migrate collectively, maintaining their apicobasal polarity, they also display a second polarity axis (front-back), characterized by actin-rich basal protrusions oriented in the direction of migration. How this front-back polarity is established and what is the guidance cue for directional migration towards the tip of villi remains unknown. Currently, we are investigating how the BM provides cues for the directional migration of epithelial cells, what are the roles of adhesive structures in reading those cues and how front-back polarity is built to allow directional cell migration. Finally, we are addressing the role of the actomyosin cytoskeleton in the maintenance of intestinal epithelium integrity and cell migration.

In collaboration with Stephanie Descroix (UMR168, IPGG), we have developed a device - reconstituted Gut-on-Chip - that will allow us to test the impact of individual parameters such as physical constraints peristalsis and the extracellular matrix (ECM) on epithelium homeostasis.