Cells have an incredible ability to find each other over great distances. During embryonic development or the spread of cancer, cells travel through complex environments to travel to precise locations with the help of chemical signals. Understanding how they use distant chemical signals to travel long distances would help us understand the mechanisms underlying human development, provide information on cancer treatment, and even one day pave the way for synthetic biology to control cell migration level.
Chemo-attractants are chemicals that cells have a tendency to move to. Just as receptors in our noses sense chemicals in the air, so receptor molecules on the surface of a cell can pick up chemoattractors that diffuse from a source. Cells move in the direction from which they pick up the strongest smell of the chemoattractor – this is how they can respond to chemical gradients. This strategy works well when the chemical source is nearby. However, just as our olfactory abilities are limited by range, gradients are much more difficult to spot at great distances. In the extreme case, the gradient can be so weak that it is imperceptible. So how do cells decide where to orientate themselves?
An emerging hypothesis is that cells manage these situations by breaking down chemoattractants in their immediate environment, creating sharp concentration gradients (differences in the concentration of chemoattractant in space) near the cell that can be used to determine direction. For example, cancerous epithelial cells break down and create gradients of chemoattractants that migrate from their primary tumors to other locations.
… these simple cellular functions may be sufficient to explain how eukaryotic cells travel long distances in complex environments
To investigate this phenomenon, a study published in Science last August challenged slime mold and cancer cells to solve complex micro-labyrinths. Scientists constructed microfluidic mazes, which consist of thin channels in a silicone mold connected to a glass petri dish, and used techniques similar to those currently used to build organ-on-a-chip models.
The researchers placed cells at the beginning of the maze and assessed their ability to make it to a large reservoir for chemoattractors at the other end. The cells detached the mazes by sensing chemoattractors along the way, moving toward them, and breaking them down. These results indicate that these simple cellular functions may be sufficient to explain how eukaryotic cells travel long distances in complex environments.
The maze setup shows how such self-generated local gradients can be used to navigate complex environments. In the team’s experiment, the concentration of the chemo-attractant was initially the same throughout the labyrinth, so that each directional gradient had to be generated by the cells themselves. In order to prevent interference between the cells during the labyrinths, the researchers mutated the cells in such a way that they could no longer produce the chemo-attractant themselves, but could still react to it and break it down.
First in the labyrinth was the slime mold Dictyostelium discoideum. This amoeba is a unicellular organism for most of its life, but it has remarkable social behavior: when hungry, thousands of slime mold cells combine over long distances to form multicellular structures. This aggregation is controlled by a chemoattractant known as cyclic AMP, which the cells produce and break down in periodic pulses.
Before attempting the whole maze, the slime mold cells first ran a race in which one group of cells was exposed to regular cyclic AMP and the other had a version that was chemically modified to be non-degradable. Cells migrated faster when they could break down cyclic AMP than when they couldn’t, which confirms the idea that cells move better towards chemicals that they can break down. The breakdown of the attractant causes the cells to move away from areas of high cell density as the amoebas break down cyclic AMP faster where there are more cells. This effect encourages the cells to detach from the starting area and keep moving forward.
Notably, Dictyostelium discoideum cells, unlike another maze-dissolving slime mold, Physarum polycephalum, which approaches the task by exploring every possible path before choosing the best, were able to avoid with their self-generated chemoattractant gradients, to take wrong paths. The researchers obtained similar results with pancreatic cancer cells isolated from mice, which also created gradients by degrading chemoattractors, suggesting that the principles examined in the study are not specific to just one cell type.
Finally, the researchers also supported their results by tricking the cells with a so-called chemoattractant “illusion”, and using computer simulations they were able to correctly predict which types of labyrinths would be easier or more difficult for the cells to solve. For example, they predicted that dead ends that branched or widened to act as reservoirs for chemoattractants would mislead more cells than short dead ends that did not contain much chemoattractant. As expected, the cells easily avoided going down short dead ends, but were more likely to be misdirected through complex, ramified dead ends. By rearranging the designs of the miniature mazes on their microfluidic chips, the researchers took full advantage of the artificial chip microenvironments to experimentally test the predictions of their computer model.
This research not only helps us understand how cells navigate complex environments to find distant sources of attractants, but can also be useful for efforts in synthetic biology such as regenerative medicine and the design of multicellular systems. In order to regrow an entire organ or to create a new biological system, cells of different types have to sort themselves out and use chemical cues to find their correct position, just like during embryonic development. Existing tools allow us to engineer cells to be attracted to chemicals to which they are naturally unresponsive. For long-distance communication, it may be equally important to teach these cells to break down their new chemoattractors.