Researchers model cues guiding cell behavior

A diverse set of physical and chemical cues act upon individual cells to ensure coordinated multicellular behavior. Using the bacterium Myxococcus xanthus, a team led by University of Georgia and Rice University researchers has devised a data-driven model of the mechanisms that guide elaborate self-organization at the cellular level.

The research, published Monday in the Proceedings of the National Academy of Sciences, provides a blueprint for future studies of more complex systems of collective cell movement.

The paper uses mathematical modeling to reconstruct the developmental pathway and build a picture of emergent cell behaviors that have remained largely unknown.

“Motile cells self-organize into elaborate and remarkably functional structures during embryonic development, tumor metastasis, the immune response, and wound healing,” said co-author and professor of microbiology Lawrence Shimkets. “There is no pre-existing mold for cells to fill. Instead, the three-dimensional structure emerges from cues passed between cells.”

To decipher the rules generating biological patterns without knowledge of the cues or cue following methods, the team looked to bacteria.

“Within the soil in your back yard lives a genus of bacteria known as Myxococcus, possibly one of nature’s earliest attempts at multi-cellular coordination. When starved, these bacteria coordinate their movement to generate a multicellular fruiting body used to help them survive the famine.”

By tracking the movement of fluorescent Myxococcus cells during fruiting body development, researchers observed minute changes in cell movement and orientation relative to the location of the emerging fruiting body.

The team discovered that the movements of individual cells within the population appeared almost random. To uncover coordinating mechanisms, the authors used computer simulations driven by the cell tracking data. This approach led to the identification of small changes in cell behavior relative to their location in the environment that, when averaged over thousands of cells, allows self-organization. The resulting computer simulations mirrored the biological results remarkably well, further supporting that small changes in the average cell behavior can lead to robust patterning at the level of the population despite the lack of compliance by many individuals.

The computer simulations revealed that three behaviors were necessary and sufficient for the pattern to form. Side-by-side alignment of many cells created prepatterns, some of which coordinated movement and provided enough topological detail to define the locations of the fruiting bodies. Then, motility of cells at the aggregation foci became sluggish leading to a buildup of cells in those locations. Outside the growing aggregates, cells biased their movement toward the aggregation foci. The simulations suggest a compensatory mechanism that would make aggregation particularly robust in the face of changing environmental conditions.

The work is notable in that none of the cues altering cell behavior nor are the mechanisms by which the cells respond to these cues are known. Nevertheless, the simulations make strong predictions about the emergent pattern-building process that can be followed up by examination of mutants that lack one of these four behaviors.

“The results suggest a more general role for these three behaviors that might provide insights into in other patterning processes such as wound healing and tumor metastasis,” Shimkets said.

The paper is available online at http://www.pnas.org/content/early/2017/05/16/1620981114.abstract

Image: Aerial view of Grand Prismatic Spring; Hot Springs, Midway & Lower Geyser Basin, Yellowstone National Park, via wikimedia commons. Photo shows steam rising from hot and sterile deep azure blue water in the center surrounded by huge mats of brilliant orange algae, bacteria and archaea.