Minuscule migrations

November 20, 2020

(Santa Barbara, Calif.) -- Cells move constantly throughout our bodies, performing myriad operations critical to tissue development, immune responses and general wellbeing. This bustle is guided by chemical cues long studied by scientists interested in cellular migration.

To better understand this phenomenon, a team of biologists and physicists, led by UC Santa Barbara's Distinguished Professor Science, are a triumph for basic research and could find applications in fields as diverse as oncology, neuroscience and developmental biology.

Directed 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 neither form nor function," said Montell, the Duggan Professor in the Department of Molecular, Cellular, and Developmental Biology. "Yet cell migration also contributes to inflammation and cancer metastasis, so understanding the underlying mechanisms has garnered substantial interest over decades."

Scientists have known for a long time that cells sense chemical attractants. Many thought a chemo-attractant gradient was all that was necessary for cells to migrate where they were needed. Yet reseachers are now looking increasingly at how the physical environment contributes to the way cells choose their paths. This presents a practical challenge, however, since reconstructing the geometry of a living tissue in an artificial environment is a tall order.

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 different factors. Within the ovary are several egg chambers consisting of 15 nurse cells and one oocyte, or developing egg cell, at one end. The nurse cells support the growth of the egg.

Around 850 follicle cells surround the nurse cells and oocyte. Of these, a group of six to eight at the tip of the egg chamber, called border cells, detached 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," Montell admits, "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."

There are two components to the border cells' migration. They clearly move from the anterior to the posterior of the egg chamber. However, what was less appreciated until now is that they also stay centrally located rather than moving to the chamber periphery on their journey, despite having roughly 40 different side paths they could take.

The researchers found that the chemo-attractant could not account for the choice of the central path -- something else must keep the border cells along their path. In fact, when they knocked out the cells' ability to detect the chemical signals, the researchers found that the cells still kept to the center of the egg chamber, although they no longer made it all the way to the oocyte at the opposite end.

The egg chamber is filled with many cells, which presents a stacking problem much like packing balls into a crate. Mathematicians have been working on problems like these for centuries and have found that there's more space in areas where more cells come together. The team confirmed this by dunking the egg chamber into a fluorescent fluid that filled the gaps between the cells.

"It seems that the border cells choose the center because it's a place where there's a tiny bit more space," said Montell. "What was most surprising is that the physical space is really tiny, much smaller than the objects moving through it. It's this tiny space that makes the difference."

Co-lead author Wei Dai, a former postdoctoral researcher in Montell's lab, carefully studied the egg chamber under the microscope and painstakingly recreated the arrangement of cells in a 3D model. This allowed the physicists on the project -- Yuansheng Cao and Wouter-Jan Rappel from UC San Diego and Nir Gov from the Weizmann Institute of Science in Israel -- to create a mathematical model of the system on which to run 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 extra bit of room between cells created an optimal path.

To ascertain that the cellar geometry really was responsible for the border cells' path, the paper's other lead author

"The tissue geometry creates a central path of least resistance, which provides directional information equally important to that provided by chemo-attractants," said Montell, adding that for 15 years chemical signals were thought to be the sole guidance cues.

She suspects a number of different factors underlie the cells' behavior. While traveling, the border cells explore their surroundings by extending small projections of the cell membrane, which are about the same scale as the gaps between the nurse cells. Additionally, the nurse cells are zipped together with proteins where they touch. By traveling through the gaps where several cells meet, the border cells don't need to break all these bonds to slip past.

The study's results make 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.

"Getting immune cells into the tumor can be a challenge, and maybe part of that is this tissue geometry challenge," Montell said. "Who would have thought that what we really need to be doing is perhaps loosening up the tumor to help the immune cells get in.

"These findings add a new concept to the way we think about what cells are attracted to and how they move around."
-end-
Note to editors: Denise Montell is available at
dmontell@ucsb.edu. Xiaoran Guo is available at xiaoran.guo@lifesci.ucsb.edu. Downloadable images can be found at TK.

University of California - Santa Barbara

Related Immune Responses Articles from Brightsurf:

Dissecting the immune characteristics of severe COVID-19 responses
A team of immunology experts from research organisations in Belgium and the UK have come together to apply their pioneering research methods to put individuals' COVID-19 response under the microscope.

Uracil switch in SARS-CoV-2 genome alters innate immune responses
Our bodies could be inducing mutations in the COVID-19 virus that activate immune cells to increase the production of pro-inflammatory molecules.

The making of memory B cells and long-term immune responses
Researchers at Osaka University in Japan have identified two factors necessary for the production of memory B cells, the cells of the immune system that allow fast responses to re-infection.

Identification of a viral factor that impairs immune responses in COVID-19 patients
A research team at The Institute of Medical Science, The University of Tokyo (IMSUT) aimed to characterize the viral factor(s) determining immune activation upon SARS-CoV-2 infection and found that ORF3b, a gene encoded by SARS-CoV-2, is a potent IFN antagonist.

Children with COVID-19 show different immune responses, but better outcomes than adults
A comparison of children and adults hospitalized with COVID-19 reveals pediatric patients, who had better outcomes and shorter hospital stays, displayed altered immune responses and more limited production of antibodies against infection.

Modeling future COVID-19 cases under a variety of immune responses, and with or without vaccines
Researchers who adapted standard epidemiological models to explore how the COVID-19 pandemic trajectory might unfold in the next five years report diverse scenarios ranging from recurring severe epidemics to elimination.

Allergic immune responses help fight bacterial infections
Researchers from CeMM, MedUni Vienna and Stanford University, have found that a module of the immune system, best known for causing allergic reactions, plays a key role in acquiring host defense against infections triggered by the bacterium Staphylococcus aureus.

Delayed immune responses may drive COVID-19 mortality rates among men and the elderly
COVID-19 (SARS-CoV-2) infections tend to be more severe among older adults and males, yet the mechanisms underlying increased mortality in these two demographics are unknown.

Detailed study of immune responses in COVID-19 patients reveals distinct 'immunotypes'
Expanding on observations made in smaller patient cohorts, researchers studying immune responses of 125 hospitalized COVID-19 patients identified distinct immune profiles -- ''Immunotypes'' -- and showed how these signatures correlated with disease severity.

Penn researchers find three distinct immune responses for sicker COVID-19 patients
Researchers from the Penn Institute of Immunology discovered three distinct immune responses to the SARS-CoV2 infection that could help predict the trajectory of disease in severe COVID-19 patients and may ultimately inform how to best treat them.

Read More: Immune Responses News and Immune Responses Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.