Leukocytes use their nucleus as a ruler to choose path of least resistance

April 03, 2019

How do mobile cell types like leukocytes or metastatic cancer cells reach their place of action during immune surveillance or cancer dissemination, respectively? The research group around Michael Sixt at IST Austria has now shown that leukocytes use their nucleus as a ruler to screen their surroundings for the largest pores--and thereby find the path of least resistance.

Certain cell types continuously crawl through the body to reach their place of action. For instance, all leukocytes--the white blood cells of the immune system--in the human body cover a cumulative distance of more than 100,000 km per hour. On their journey, these migratory cells have to find their way through a three-dimensional maze crowded with other cells and extracellular matrix. Certain cell types--mesenchymal cells like fibroblasts--move forward by digesting the tissue they come up against, thus leaving behind a tunnel as a wake of devastation. Leukocytes, on the other hand, show an amoeboid way of movement that allows them to move around 100 times faster. Also, they do not digest or remodel their environment (if they did, they would perforate the body with more than two million kilometers of tunnels per day!). How these extremely fast cells navigate through the dense meshwork of interstitial connective tissue fibers without harming other cells has been of great interest to cell biologists. Professor Michael Sixt and his team--including first author Jörg Renkawitz, Postdoc at IST Austria at the time of the study and now leading his own research group at the Biomedical Center of Ludwig-Maximilians-University in Munich, Germany--have now found out how leukocytes manage to choose the path of least resistance when navigating through complex environments.

Nucleus measures pore size and helps leukocytes to move full speed ahead

To understand the mechanism behind this selective form of cell movement, the researchers built an obstacle course for leukocytes in reconstituted tissue where the cells could choose between differently sized pores while following global directional cues such as chemotactic gradients. What they observed was that whenever the amoeboid cells had a choice, they used the bigger pores, i.e. the path of least resistance. In further tests, the scientists found that the cells facilitate this active directional movement by pushing their nucleus very much to the front of the cell so it can serve as a kind of mechanical gauge or ruler. In other words, as the cell is moving forward, it applies cytoskeletal forces to insert its nucleus into several adjacent pores to measure pore sizes. Michael Sixt: "The usual organelle to steer a cell is the actin rich leading front, which explores the environment. Unexpectedly, we found that this is not what determines the path of a leukocyte. Instead, it is the nucleus that guides the cell through the bigger pores. This makes sense as the nucleus is the most bulky part of the cell and also sensitive to damage."

Microtubules make sure that cells are not fragmented when passing through pores

Whenever the cells successfully push their nucleus through a pore, they have to retract the nucleus-free protrusions, which are still inserted in the other pores, to avoid becoming entangled or even fragmented. To tell the protrusions to retract, the microtubules disappear from these protrusions as soon as the microtubule organizing center (which always follows the nucleus) passes through a pore. This disappearance of the microtubules triggers actomyosin contraction and the cell finally retracts the remaining protrusions. When the researchers actively destroyed the microtubules, the cells entangled because the supernumerary protrusions had not retracted, kept moving forward through other pores and migrated in many directions. Ultimately, the cell fractured into pieces and died. "Our findings are based on the analysis of leukocytes. Yet, most probably, the mechanisms are the same for any other amoeboid cell types involved in developmental, immunity or regeneration processes. Also, the mechanism might help to explain how cancer cells move from one part of the body to another to form metastases and, most importantly, how to stop them from doing so," Michael Sixt concludes.
-end-
The study was partly supported by data from collaborators at the University of Texas Southwestern Medical Center, Dallas, USA. Michael Sixt's work for this study was supported by the European Research Council (ERC), a grant from the Austrian Science Foundation (FWF) and the FWF DK "Nanocell". Jörg Renkawitz was supported by ISTFELLOW funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013), and an EMBO long-term fellowship co-funded by the European Commission.

IST Austria

The Institute of Science and Technology (IST Austria) is a PhD-granting research institution located in Klosterneuburg, 18 km from the center of Vienna, Austria. Inaugurated in 2009, the Institute is dedicated to basic research in the natural and mathematical sciences. IST Austria employs professors on a tenure-track system, postdoctoral fellows, and doctoral students. While dedicated to the principle of curiosity-driven research, the Institute owns the rights to all scientific discoveries and is committed to promote their use. The first president of IST Austria is Thomas A. Henzinger, a leading computer scientist and former professor at the University of California in Berkeley, USA, and the EPFL in Lausanne, Switzerland. The graduate school of IST Austria offers fully-funded PhD positions to highly qualified candidates with a bachelor's or master's degree in biology, neuroscience, mathematics, computer science, physics, and related areas. http://www.ist.ac.at

Animal welfare

Understanding cell biological processes is only possible by studying real cells and the natural physiological environments of organisms, in this case of mice. No other methods can serve as alternatives. The animals were raised, kept and treated according to the strict regulations of Austrian law.

Institute of Science and Technology Austria

Related Cell Types Articles from Brightsurf:

AI methods of analyzing social networks find new cell types in tissue
In situ sequencing enables gene activity inside body tissues to be depicted in microscope images.

A new strategy of cell entry for some types of parvoviruses
Researchers at the Institut national de la recherche scientifique (INRS), in collaboration with American scientists, have uncovered a new parvovirus strategy for reaching the cell nucleus which is their site of replication.

Brain cell types identified that may push males to fight and have sex
Two groups of nerve cells may serve as ''on-off switches'' for male mating and aggression, suggests a new study in rodents.

Yale, Baylor study reveals new cell types in lethal lung disease
A research team from Yale and Baylor College of Medicine has completed the largest single-cell analysis to date of lungs affected by Idiopathic Pulmonary Fibrosis (IPF), revealing how cells change in response to the disease and identifying previously unknown cell types.

Novel software reveals molecular barcodes that distinguish different cell types
A new set of computational methods developed at Baylor College of Medicine allows researchers to identify cell-type specific methylation patterns -- molecular barcodes -- in complex cell mixtures.

Scientists devise new 'bar code' method to identify critical cell types in the brain
A discovery by researchers at Brown's Center for Translational Neuroscience could pave the way for future studies aimed at developing solutions to ALS and other vexing neuromuscular diseases.

AI successfully used to identify different types of brain injuries
Researchers have developed an AI algorithm that can detect and identify different types of brain injuries.

Eclectic rocks influence earthquake types
New Zealand's largest fault is a jumble of mixed-up rocks of all shapes, sizes, compositions and origins.

New knowledge on how different brain cell types contribute to our movements
Researchers at Karolinska Institutet have mapped how different nerve cells in the brain area striatum process information to plan and execute our movements at just the right time and with the right vigour.

Three types of cells help the brain tell day from night
Researchers at the Salk Institute report the discovery of three cell types in the eye that detect light and align the brain's circadian rhythm to our ambient light.

Read More: Cell Types News and Cell Types 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.