Cells often sense their surrounding microenvironment, including biochemical signaling gradients, and then use that information to change their behavior. Many cell types chemotax, which means they move toward regions with higher chemical concentration. Sometimes cells need more information about these chemical gradients than what they can determine individually, necessitating cluster formation to better integrate information from their environment. In addition, many cell types move inside a confluent tissue, where there are no gaps or overlaps between the cells, which requires a different type of mechanical model than for clusters moving in empty space. In the dense case, cells migrating through signaling gradients can disrupt the chemical concentration as they carry, or advect, the chemical as they move. This leads to a feedback loop in which cell clusters integrate information about a signaling gradient to move collectively, and then those motions alter the gradient, which could potentially disrupt cluster movement. Therefore, our goal was to investigate how chemical gradients affect collective motion of confluent clusters of cells and understand how advection from cluster migration in turn affects the biochemical gradient.

The cover image of the December 6 issue of Biophysical Journal depicts a vertex model simulation of a cluster of confluent epithelial cells migrating in a biochemical signaling gradient. The artistic representation of simulation data is by Melanie Oventhal. The color represents the change in the biochemical concentration from steady state because of the advection of the signal by cells as they move. Warmer colors represent a larger change from steady state.

The advection is generated by a cluster of chemoreceptive cells (middle right) that create a sharp interface between the cells and the surrounding tissue, which is composed of cells that are not chemoreceptive. Although individual chemoreceptive cells cannot climb the gradient, the cluster uses simple rules (such as a confluent version of contact inhibition of locomotion) to propel itself up the gradient and pull chemical concentration with the cluster as it migrates. This creates a “sun-like” coloring around the cluster as a region of higher concentration follows the cluster.

Although our research is purely theoretical, there are hints from experiments that the mechanisms we propose could be driving collective chemotaxis observed in several confluent tissues, including the Drosophila ovary, Xenopus neural crest cells, and lymphocytes. It would be interesting to test this hypothesis quantitatively in future experiments. We also provide our open-source computational code, which couples a chemical concentration field to a mechanical vertex model for tissues, to allow others to study alternative collective migration rules. Although this work focuses on chemotaxis, it is a good example of the general principle that simple interaction rules can lead to complex and perhaps unexpected collective behavior.

You can read more about our research on our group website: https://mmanning.expressions.syr.edu/.

 — Elizabeth Lawson-Keister and M. Lisa Manning