New cells edge towards their preferred positions in tissue

Tech Science 8. jan 2023 3 min Associate Professor Jakub Sedzinski Written by Kristian Sjøgren

Researchers have discovered how new cells use finger-like protrusions as they probe their microenvironment when migrating towards integration within tissue. Researchers say that this is like attending a rock concert and trying to get to the front row.

When new cells are created – in the skin, the respiratory tract, in the organs and everywhere else – they must move from the lower layers of the tissue to the place where they execute their function.

Researchers have understood well the biochemical signals that cause cells to migrate within the tissue, and now researchers have also determined how this happens mechanically.

A new study shows that the cells make finger-like protrusions called filopodia to both sense the cellular microenvironment and edge forward between neighbouring cells until they reach their preferred position for integration into the tissue.

The discovery advances researchers’ knowledge of various diseases and on the formation of tissue during embryonic development or when tissue needs to be repaired or replaced.

“Cancer cells use similar finger-like protrusions when they invade tissue and metastasise. Our discovery may therefore contribute to understanding how cancer metastasises and may also be used as a diagnostic tool to monitor the progression of cancer,” explains a researcher involved in the study, Jakub Sedzinski, Associate Professor, Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), University of Copenhagen.

The research, which was Jakub Sedzinski has done in collaboration with PhD student Guilherme Ventura, Dr. Aboutaleb Amiri, Assistant Prof. Amin Doostmohammadi, among others, has been published in Nature Communications.

Like attending a rock concert

To learn more about the mechanics of cell migration through a tissue, the researchers studied the skin from frog embryos.

The skin of frogs is very comparable to the tissue in the human respiratory tract. This makes the tissue relevant to study to learn more about the tissue aspect of human lung diseases such as asthma or chronic obstructive pulmonary disease.

In studying cell migration in the embryos, the researchers investigated a common phenomenon to all types of tissue in which stem cells divide and become tissue-specific cells that migrate from deep in the tissue to the surface, where the cells execute their function.

The researchers used confocal microscopy and camera technology, similar to that used during football matches, to track the migration of the cells in extremely high resolution, to see not only that the cells moved but also how they did it.

“The migration of the cells is similar to attending a rock concert: you are surrounded by people and want to get to the front row and the best view. The cells have the same problem. They are also surrounded by other cells that block the way forward or push and pull on them,” says Guilherme Ventura.

Sensing the microenvironment

The microscopic examination showed that cells make filopodia when they migrate from the back row of the tissue to the front row.

They use them to sense the microenvironment, the neighbouring cells in it and the tissue as a whole.

The filopodia also actively grasp the surrounding cells and pull the cell forward, just as you might to get to the front row at a rock concert.

Further, the researchers determined that the cells probe the stiffness of the tissue to identify the preferred positions for cell integration. This tells the cells their location in the tissue.

When they find a place with the right stiffness, the cells are ready to integrate into the tissue. Then they stop making the filopodia and change shape to a hexagonal structure that fits between the other cells.

“The stiffness of the tissue is a signal to the cells they can monitor. They seek to be integrated in the tissue where it is most rigid. Once there, they stop making filopodia and start growing instead,” explains Jakub Sedzinski.

May be clinically relevant

The discovery makes the researchers more aware of how tissue is formed in fetal development and when damaged tissue needs to be repaired or replaced.

The same mechanisms also operate when cancer cells penetrate tissue and metastasise. Similar to healthy cells, the cancer cells seek areas in the tissue with specific properties that make settling down and spreading easier for them.

The discovery also makes the researchers more aware of the mechanistic properties of the tissue in, for example, asthma, in which the lung tissue is more fluid and less rigid than in healthy tissue.

The researchers therefore consider that this discovery may be clinically relevant.

“Envision being able to develop drugs that can affect the ability of cells to make filopodia. If we can purposefully prevent cells from making them, we can also inhibit cancer cells from migrating. We can also envision loading cells with medicine and, with the help of their filopodia, guiding the cells to the place in the tissue where the medicine will be effective,” concludes Jakub Sedzinski.

Multiciliated cells use filopodia to probe tissue mechanics during epithelial integration in vivo” has been published in Nature Communications. Jakub Sedzinski was supported by the Leo Foundation and the Novo Nordisk Foundation; Amin Doostmohammadi was supported by the Villum Fonden, the European Union through an ERC Starting Grant PhysCoMeT and the Novo Nordisk Foundation, which has also awarded grants to the Novo Nordisk Foundation Center for Stem Cell Biology (DanStem) and the Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW).

The Sedzinski group aims to understand the general principles underlying epithelial homeostasis. Particularly, they want to determine both the mechani...

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