Intestinal epithelial cells undergo high turnover, which is important for intestinal epithelium homeostasis and function. This continual cell renewal depends on the activity of stem cells that reside at the crypt base, which generate a highly proliferative population of cells that progressively differentiate while moving upwards along the villi, to be shed at the villi tips a few days later. It has been proposed that this epithelial migration along the villi is passive and driven by pushing forces generated by dividing stem cells. Krndija et al. now demonstrate the role of active collective cell migration in this process.
Short-term inhibition of proliferation does not block epithelial cell migration along the villi, leading the authors to hypothesize the involvement of active migration. Measuring cell density along the villi in mouse small intestines revealed an initial decrease in cell numbers starting from the crypt, followed by a gradual increase in the upper region of the villi. According to a biophysical model of intestinal epithelium dynamics that the authors developed, this cell density profile indicates a two-tier model of cell migration in the intestinal epithelium, whereby both stem cell division-derived forces (close to the crypt) and active cell migration (along the villi) are involved.
Live-cell imaging of mouse intestinal explants showed that cells maintained their cohesiveness when moving along the villi, indicating that they migrate collectively. Moreover, the measured mechanical tension in the epithelial sheet was highest at the back of the sheet (at the bottom of the villi), which is consistent with tensile stresses observed in collectively migrating epithelial sheets in vitro.
Super-resolution microscopy further revealed that epithelial cells moving along the villi extend — at their basal surface — small, actin-based protrusions that point towards the direction of movement. Short-term inhibition of the Arp2/3 complex — which nucleates branched actin networks important for cellular extensions — disrupted the polarity of these basal protrusions, reduced intra-epithelial tension and hindered cell migration. The inhibition of cell migration was more pronounced in the upper part of the villi, in accordance with the proposed two-tier model of epithelial cell migration in the intestine.
“epithelial cells moving along the villi extend … small, actin-based protrusions”
Thus, active collective cell migration contributes to intestinal epithelial turnover. It will now be important to understand how this active cell migration is regulated (for example, in terms of directionality) and whether its deregulation might lead to intestinal dysfunction.
Krndija, D. et al. Active cell migration is critical for steady-state epithelial turnover in the gut. Science 365, 705–710 (2019)