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Intestinal homeostasis and active cell migration

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Active cell migration would appear to play a crucial role in homeostatic renewal in the adult intestinal epithelium according to the findings to come out of a new study published in Science and conducted by Denis Krndija, a researcher in Danijela Matic Vignjevic’s team at the Research Center. These findings open up new possibilities in regulating this complex homeostatic process, and disruption triggered by cancer.

Drawing on a combination of biophysical modelling and 3D quantitative tissue imaging, as well as physical and genetic manipulations in mice, Denis Krndija and his co-authors from the cell invasion and migration team overseen by Danijela Matic-Vignjevic at the Research Center and in collaboration with Edouard Hannezo (Institute of Science and Technology, Austria) uncovered the existence of a migratory force active during homeostatic* epithelial renewal, in findings published in the Science journal. “This active migratory force is dependent on actin cytoskeleton dynamics induced by the Arp2/3 protein complex, a key factor in actin nucleation”, explains post-doctoral researcher Denis Krndija. The team analyzed cellular speed and tissue tension and density along the intestinal villi in order to quantitatively determine the equilibrium of both mitotic and active migratory forces in epithelial homeostasis. They demonstrated that mitotic pressure has a limited, short-range effect, restricted to the lower areas of the intestinal villi, where cells migrate more slowly. In the rest of the villi, however, cells migrate actively, using cellular protrusions.

However, according to CNRS team leader Danijela Matic-Vignjevic (UMR144 CNRS/Institut Curie cellular biology and cancer), “if this complex homeostatic process isn’t properly controlled, it can lead to high probability of failure, therefore resulting in pathologies such as tumors and inflammatory diseases”. The translational impact of this research was further explored by Dr. Marnix Jansen (University College London, United Kingdom) in the same issue of Science, offering up new prospects in research into colorectal cancer.

Over and above the key role it plays in absorbing nutrients, the intestinal epithelium serves as a barrier against bacterial, biochemical and mechanical attacks in its lumen’s harsh environment. The small intestine’s epithelium comprises a single layer of cylindrical cells that cover the intestinal villi, projections that protrude out into the intestine’s lumen, as well as crypts, small invaginations in the underlying connective tissue containing stem cells.

Cell migration at the heart of intestinal homeostasis

All epitheliums are continuously self-renewing, powered by mitotic stem cell division. According to Denis Krndija, “the intestinal epithelium is the body’s fastest self-renewing epithelium – we get a brand-new epithelium every week!”. The cycle starts via cell division in the crypts, after which the cells migrate upwards along the villi. Cell migration is therefore a key process in epithelial renewal. It had previously been thought to be a passive process, induced by the force generated by cell division in the crypts.

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Active cell migration is critical for steady-state epithelial turnover in the gut