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The secret of the power of the white cell

Scientists from the Weizmann Institute discovered that the flexible nuclei of the white blood cells can squeeze through the "fence" of the cells lining the blood vessels, while partially breaking down the intracellular skeleton of these cells and rebuilding it - and thus they allow the cells of the immune system to reach their destination. 

A white globule is pushed through endothelial cells on its way out of blood vessels. The intracellular skeleton (actin fibers) of the spherule and of the endothelial cells is exposed during the treatment. The location of the globule nucleus is shaded in brown and the globule branch that penetrated through the endothelial cells and is rich in actin fibers is shaded in yellow.
A white globule is pushed through endothelial cells on its way out of blood vessels. The intracellular skeleton (actin fibers) of the spherule and of the endothelial cells is exposed during the treatment. The location of the globule nucleus is shaded in brown and the globule branch that penetrated through the endothelial cells and is rich in actin fibers is shaded in yellow. Source: Weizmann Institute magazine.

One of the great puzzles concerning the living body is related to cell migration: how can cells of different types move between areas of the body, and jump over obstacles and fences along the way, as part of normal or pathological activity? A new study by researchers from the Weizmann Institute of Science sheds light on this issue, by focusing on the migration of the cells of the immune system in the body. In the study, it was discovered that white blood cells are able to actively open large holes in the inner wall of blood vessels - with a diameter of several microns - in order to squeeze through these openings and reach areas of inflammation.

Prof. Ronen Alon and the members of his research group, from the department of immunology at the institute, discovered that the white blood cells penetrate the "hedge" of the cells that line the blood vessels (endothelial cells) by pushing their nuclei between these cells or even into them, while breaking down their intracellular skeleton and breaking open Openings through which they thread inside. This activity is possible, among other things, thanks to the fact that the nucleus - the largest and hardest organelle in the living cell - is softer and more flexible in white blood cells, but rigid enough to break through the blood vessel buffer. The scientists, who sought to understand this mechanism, followed in real time and simultaneously the behavior of the nuclei in different white blood cells, and the actin fibers that make up the skeleton of the endothelial cells. To this end, the researchers used fluorescence microscopy in combination with electron microscopy, in collaboration with Dr. Eugenia Klein from the microscopy unit, as well as systems that simulate blood vessels in a test tube and imaging experiments in mice. The study, which is also shared by research students Sagi Barzilai and Francesco Roncto, and postdoctoral researcher Sandeep Kumar Yadav, was recently accepted for publication in the scientific journal Cell Reports.

Many studies are devoted to the relationship between the white blood cells and the endothelial cells. However, while in previous studies, including those of Prof. Alon and his research team, the emphasis was placed on the active role of the endothelial cells, in this study the spotlight was turned on the white blood cells, which turned out to be active players in the migration process. For example, the popular concept in this field was that white blood cells penetrate through the blood vessel wall through muscle-like contraction mechanisms that the endothelial cells activate on themselves, to help the white blood cells reach the target tissue. But in the current study no evidence of this was found. "The innovation here is in the active role of the immune cells in the process of crossing through the blood vessels," says Prof. Alon. "Many thought that the endothelial cells help in this process, but we have shown that they do present stop signs and penetration to the certain white blood cells, but the immune cells are the ones that 'do the work' - and level the transition themselves."

For two decades Prof. Alon's laboratory has been engaged in the study of the migration of various immune cells - essential studies for the study of infectious diseases and autoimmune diseases. For example, in previous studies it was discovered that white blood cells navigate their way out of the bloodstream towards sites of inflammation using "exit signs" - chemical signals that mark the site of inflammation - and that the white blood cells establish their grip on the inner wall of blood vessels using dozens of small "legs" which help identify the "exit signs" displayed on the surface of the endothelial cells.

Beyond a better and more accurate understanding of how the immune system works, the findings in this study can help in the study of cancer diseases. Following the research, the question arises, can metastatic cancer cells adopt the efficient and rapid penetration of white blood cells through blood vessels, and if so - when and how. "The research has important implications for the study of metastatic cells," says Prof. Alon. "We hypothesize that the minority of these cells adapts mechanisms similar to those used by the immune cells. If we understand how they do this, we may also be able to disrupt the ability of this minority to cross blood vessels and establish metastases."

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Crossing blood vessels by a white blood cell takes 3-10 minutes. Cancer cells sometimes need hours to complete a similar crossing.

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