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Cells are constantly moving throughout our body, performing a myriad of operations critical to tissue development, immune responses, and general well-being. This commotion is driven by chemical signals long studied by scientists interested in cell migration.
To better understand this phenomenon, a team of biologists and physicists, led by the distinguished Professor Denise Montell of UC Santa Barbara, studied the effect that the geometry of the biological environment has on cellular movement. Using mathematical models and fruit flies, the team found that physical space has a lot of influence on cell migration. That is to say, the geometry of the tissue can create a path of least resistance, which guides cell movement. 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.
Direct cell migration is an essential feature of biological processes, both normal and pathological. “Without directional cell migration, embryos would not develop, wounds would not heal, and the immune and nervous systems would not form or function,” said Montell, Professor Duggan of the Department of Molecular, Cell and Developmental Biology. “Yet cell migration also contributes to inflammation and cancer metastasis, so understanding the underlying mechanisms has garnered considerable interest over decades.”
Scientists have known for a long time that cells perceive chemical attractants. Many thought that a chemo-attractive gradient was all that was needed for cells to migrate to where they were needed. Yet researchers are now increasingly examining how the physical environment contributes to how cells choose their pathways. This presents a practical challenge, however, as reconstructing the geometry of a living tissue in an artificial environment is a daunting task.
Montell’s team experimented with the ovaries of fruit flies, one of the earliest and best-studied models of cell migration, to uncover the contributions of multiple different factors. Inside the ovary there are several egg chambers made up of 15 nurse cells and an oocyte, or developing egg cell, at one end. Nurse cells support egg growth.
The boundary cells make their way between the nurse cells to reach the oocyte.
Photo credit: DENISE MONTELL
About 850 follicular cells surround the nurse cells and oocytes. Of these, a group of six to eight at the far end of the egg chamber, called boundary cells, break off and migrate between the nurse cells towards the oocyte, where they are critical in the final development of the egg.
This system not only provides a perfect model for studying cell movement in general, but the boundary cell cluster behaves much like cancer in metastases. “At first, the system might seem very dark and arcane to spot out of thin air,” Montell admits, “but apparently, Mother Nature reuses things and the mechanisms these cells use to move are very similar, even in molecular detail. about how cancer cells move. “
There are two components in border cell migration. They clearly move from the front to the back of the egg chamber. However, what has been less appreciated until now is that they also remain centrally located rather than moving to the periphery of the chamber during their journey, despite having around 40 different side paths they could take.
The researchers found that chemo-attractant could not explain the choice of the central path: something else must keep the boundary cells along their path. In fact, when they eliminated the cells’ ability to detect chemical signals, the researchers found that the cells still remained in the center of the egg chamber, although they no longer made it to the oocyte at the opposite end.
The egg chamber is filled with many cells, which presents a stacking problem very similar to packing balls in a crate. Mathematicians have been working on problems like these for centuries and have found that there is more room in areas where more cells congregate. The team confirmed this by immersing the egg chamber in a fluorescent fluid that filled the spaces between the cells.
“It seems that the border cells choose the center because it is a place where there is a bit more space,” Montell said. “The most surprising thing is that physical space is really tiny, much smaller than the objects that move through it. It is this small space that makes the difference “.
Lead co-author Wei Dai, a former postdoctoral researcher in Montell’s lab, carefully studied the egg chamber under a microscope and painstakingly recreated the cell arrangement in a 3D model. This allowed project physicists – Yuansheng Cao and Wouter-Jan Rappel of UC San Diego and Nir Gov of the Weizmann Institute of Science in Israel – to create a mathematical model of the system on which to run the simulations.
Montell’s son, a technical director at Pixar Animation Studios, was then able to superimpose the results of the mathematical model onto the 3D recreation of the egg chamber. The results supported the hypothesis that the little extra space between the cells created an optimal path.
Boundary cells follow chemical and geometric cues to navigate between nurse cells through the center of the egg chamber to the oocyte at the opposite end.
Credit: BRANDON MONTELL
To ascertain that the geometry of the cellar was indeed responsible for the path of the boundary cells, the paper’s other lead author Xiaoran Guo, a doctoral student in Montell’s lab, examined mutated egg chambers with 31 nurse cells, al contrary to the usual 15. In these more crowded cases, the boundary cells still chose a path through the area with the most cellular junctions, rather than the physical center of the egg chamber.
“The geometry of the tissue creates a central path of least resistance, which provides directional information just as important as that provided by chemo-attractants,” Montell said, adding that for 15 years it was thought that chemical signals were the only driving signals. .
He suspects that several factors underlie the behavior of the cells. During the journey, the boundary cells explore their surroundings by extending small projections of the cell membrane, which are roughly the same scale as the spaces between the nurturing cells. In addition, the nurse’s cells are compressed together with the proteins where they touch. By traveling through the cracks where different cells meet, the boundary cells don’t need to break all these bonds to slide past.
The results of the study make it clear that scientists must consider the influence of the physical environment for all kinds of instances where cells migrate through confined spaces; for example, the development of the brain or the movement of immune cells through lymph nodes and tumors.
“Getting the immune cells into the tumor can be a challenge, and perhaps part of that is this tissue geometry challenge,” Montell said. “Who would have thought that what we really need to do is perhaps dissolve the tumor to help the immune cells enter.
“These findings add a new concept to the way we think about what cells are attracted to and how they move.”
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