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How cells communicate with each other

The ability of cells to move around as a cohesive group and communicate with each other plays a major role in many vital processes, including wound healing and embryo development. One cell becomes a lead cell and determines the direction that follower cells take. Researchers led by biophysicist Joachim Spatz from the Max Planck Institute for Intelligent Systems in Stuttgart have successfully decoded the collective movement of cells in the body. Working with an interdisciplinary team of researchers, Spatz has found out that a protein called merlin plays a key role in collective cell migration. The protein registers whether a neighbouring cell is moving and in what direction it is going.

For the past decade or so, Prof. Dr. Joachim Spatz, director of the Max Planck Institute for Intelligent Systems in Stuttgart, has been studying the mechanisms that enable cells to adhere to tissue or move around – initially at individual cell level and then at cohesive group level. "We are interested in looking at how many cells communicate with each other in such collectives, and how they come up with a coordinated solution," says Spatz describing the approach pursued by his interdisciplinary group of researchers, which includes physicists, biologists and medical doctors. He adds: "If you cut yourself and the skin needs to heal, the wound-healing process benefits by cells being able to move as a cohesive group."

Cohesive migration of cells is also important in embryo development, starting with a single cell, and rapidly growing into a cell collective. Another interesting observation is that tumour cells struggle to penetrate and proliferate in tissue in collective form. Spatz explains: "The situation is completely different in tumours. Tumour cells are much less likely to form metastases when they are organised in a group." Detailed insights into the mechanisms that govern the collective movement of cells is therefore of key importance.

Prof. Dr. Joachim P. Spatz is director of the Max Planck Institute for Intelligent Systems. Amongst other things, he studies how cells move in collectives, enabling them to seal wounds quickly and effectively. © Max Planck Society

Lead cells appear from all kinds of places

The researchers from Stuttgart have carried out a number of different experiments to find out how collective cell migration works. Using a fluorescence microscope, they have observed a group of around one hundred cells in a Petri dish moving in one direction for a short time. A few cells always appeared to lead the cell collective, and are referred to as lead cells. "These observations led to two major research questions," says Spatz. "Firstly, we were interested in the mechanisms that determined which cells became lead cells and which became followers. And secondly, we wanted to find out how the lead cell communicated with the follower cells."

The researchers have found out that cell migration follows the principle of cell mechanics: the cytoskeleton gives a cell mechanical stability. This stability is registered by the cell's neighbours, resulting in the alignment of the cells' movements and the formation of a distinct border as a group of cells moves forward. Spatz explains the phenomenon as follows: "It's like a herd of cattle or a flock of sheep inside a paddock. The question is, which animal will be the first to break through the fence? Our experiments have shown that it depends on the shape of the fence. If, for example, the fence has a distinct corner, then it will easily break at that point because there is a strong bend." Cells in the corners of a collective are the preferred lead cells. This means that cells can be turned into lead cells in the Petri dish by creating a specific surface pattern with corners.

 

Left: Merlin (green) is located in the membrane of cells that do not move (cell nucleus is stained red). Right: Merlin leaves the membrane in migrating cells. © Spatz

Communication by way of merlin

The researchers found that the cells located in the corners of a cell collective are the fastest; they act as lead cells. However, the lead can be taken by any other cell at any time. "The cells virtually fight over the lead. It's an exciting, competitive process. Just like everyday life," says Spatz. However, the lead cells stay mechanically connected to their follower cells by cell-to-cell contacts. The forward motion of the lead cell puts mechanical tension on the follower cells, thus enabling the cells to communicate with each other. The researchers have now found that a membrane-cytoskeleton scaffolding protein called merlin, which stands for moesin-ezrin-radixin-like protein, senses the mechanical tension and controls the collective migration of cells.

Merlin is also a known tumour suppressor. The researchers from the Max Planck Institute for Intelligent Systems in Stuttgart have shown for the first time ever that merlin is also able to leave the cell membrane. While the cell is stationary, merlin stays in the membrane. However, when mechanical tension is created as the neighbouring cell starts moving, merlin leaves the membrane. Cell communication is thus an active process: the lead cell triggers the molecular process, the mechanical impulse is registered and the neighbouring cell can follow the lead cell. Merlin is thus a sensor, and inhibitor, that detects external tension. It detaches from the membrane, thus allowing other proteins to attach to it. It is not yet known what subsequently happens to merlin. "The protein is later found in the cell nucleus. But we do not know whether it is recycled there or whether new merlin proteins are produced," says Spatz.

Active substance to promote healing

The researchers have demonstrated how cells communicate with each other in cell culture dishes, and now hope to investigate the process on real skin. They plan to work with Professor Niels Grabe from Heidelberg University Hospital, who is a specialist in skin models and evaluating them. The researchers have created a wound and monitored the healing process over several days. They found that the protein merlin also played an important role in wound healing.

The two research groups will now use the skin models to find out how the wound healing process can be influenced and turned into a constructive healing process. Professor Spatz hopes to be able to turn their findings into clinical application as quickly as possible. One idea is to develop a functional wound dressing for treating life-threatening or chronic wounds.

 

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