Cells are constantly moving throughout our bodies, performing functions crucial to tissue development, immune responses and general wellbeing. This locomotion—an essential feature of biological processes, both normal and pathological—is guided by chemical cues long studied by scientists interested in cellular migration.
But a team of physicists and biologists at UC San Diego and UC Santa Barbara took a different route by investigating the effect that the geometry of the biological environment has on cellular movement. Using mathematical models and fruit flies, the group discovered that the physical space influences cell migration, too. Namely, tissue geometry can create a path of least resistance which guides cellular motion. These insights, published in the journal Science, are a triumph for basic research and could find applications in fields as diverse as oncology, neuroscience and developmental biology.
Before the study, according to UC San Diego Physicist Wouter-Jan Rappel, it was believed that chemical gradients, or chemo-attractants, were sufficient to guide the migration. The study’s findings, however, show that topography—the surface features of cells—can be a determining factor as well, selecting a path of least resistance concentrated near the center of the egg chamber.
In the fruit fly, around 850 follicle cells surround the nurse cells and oocyte—an immature cell. Of these, a group of six to eight at the tip of the egg chamber, called border cells, detach and migrate between the nurse cells to the oocyte where they are critical in the final development of the egg. Not only does this system provide a perfect model for studying cellular motion in general, the border cell cluster behaves very similarly to metastasizing cancer.
“At first, the system might seem very obscure and arcane to pick out of the blue,” said Denise Montell, UC Santa Barbara’s Duggan Professor in the Department of Molecular, Cellular and Developmental Biology, who led the study, “but as it turns out, Mother Nature reuses things, and the mechanisms that these cells use to move are very similar, even in molecular details, to how cancer cells move.”
Montell explained that without directional cell migration, embryos would not develop, wounds would not heal and the immune and nervous systems would neither form nor function. “Yet cell migration also contributes to inflammation and cancer metastasis, so understanding the underlying mechanisms has garnered substantial interest over decades,” she said.
Looking at how the physical environment contributes to the way cells choose their paths presents a practical challenge, however, since reconstructing the geometry of a living tissue in an artificial environment is a tall order. This is why Montell’s team experimented with the ovaries of fruit flies—one of the earliest and best-studied models of cell migration—to tease out the contributions of multiple factors.
Rainbow display of 99 simulated migration paths (red=start and blue=end) for each of the indicated conditions. Only the control condition, during which path selection is a function of both a posterior chemoattractant gradient and topographical cues, results in migration paths that are consistent with experimental results. Video courtesy of Wouter-Jan Rappel, UC San Diego Physics.
“Most of our previous research involves looking at single cell migration in the presence of chemical gradients,” explained Rappel. “The problem of border cell migration in Drosophila (common fruit fly) was appealing to us since it involves a small group of cells in a complex environment. The results of Prof. Montell’s group were really exciting and interesting, since they showed that chemical guidance could not explain all the results. Therefore, to fully comprehend the results we needed to propose and test a novel mechanism.”
According to Rappel, mechanical events play an essential role in cell migration, which can be described using a physics framework—specifically, the generation of protrusive, contractile, and adhesion forces. So the team used physics-based concepts to determine the energetic penalties for a group of cells that moves into spaces, or voids, between much larger cells.
The research scientist in the UC San Diego Department of Physics explained that with this approach, the scientists were able to show that spaces formed by junctions of more than two cells are energetically favored over the more commonly present two-junction spaces. Professor Nir Gov, Department of Chemical Physics at Weizmann Institute of Science in Israel, contributed to this aspect of the research. The team then used a dynamical model, also based on energies and forces, to determine how this group of cells migrates through experimentally determined topographies of the egg chambers. Rappel and his postdoctoral scholar Yuansheng Cao demonstrated that that the experimental topography results in paths that are located at the center of the egg chamber.
The study makes it apparent that scientists need to consider the influence of the physical environment for all kinds of instances where cells migrate through tight spaces; for example, the development of the brain or the movement of immune cells through lymph nodes and tumors.
The researchers believe that their findings can have significant implications in several biological processes, including cancer cell metastasis. There, cells and small groups of cells navigate through a complex environment. Understanding how this navigation depends on the topography can have therapeutic implications.
This research was supported by the National Institutes of Health (grant no. GM46425), the National Science Foundation (grant no. PHY-1707637), the American Chemical Society (grant no. PF-17-024-01-CSM); use of the NRI-MCDB Microscopy Facility and the Imaris computer workstation was supported by the Office of The Director, NIH (award no. S10OD010610).