Researchers have long wondered how our cells navigate inside the body. Two new studies, in which Lund University researcher Pontus Nordenfelt has participated, have now demonstrated that the cells use molecular force from within to steer themselves in a certain direction. This knowledge may be of great significance in the development of new drugs.
Pontus Nordenfelt, researcher in infection medicine at Lund University in Sweden, has previously shown how cells can move inside the body, a process known as cell migration. By bracing itself against the underlying surface, and pushing with its front part while releasing the back, the cell gains force that enables it to move.
Pontus Nordenfelt, together with international research teams, has now studied how the cell navigates inside the body. Cells interact with their environment with the help of integrins – molecules which are situated in the cell membrane and have contact with both the exterior and interior of the cell.
"The integrins can essentially be found on all of our cells and are important in all types of cell interactions. This makes them a regular target for drugs used to treat many different diseases. That's why it's so important to learn how they work," says Pontus Nordenfelt.
When the integrin is inactive it folds together, and when it is active it stretches out on the outside of the cell. This is something that has left researchers wondering: why does it do that?
"The cell tests different surfaces in its vicinity by pressing on them with the integrins. The integrins are like small anchors or hooks that unfold when active, and collapse when inactive," explains Pontus Nordenfelt.
While the integrins unfold and get a sense of what is on the outside of the cell, they can use force from within to become fully active. The power that is formed can then steer the cell in different directions by aligning the integrins. The fact that the force applied on the outside of the cell can be controlled from the inside was unexpected.
"So the cell might actively say it wants to test a surface, and this is mechanically controlled from within the skeleton of the cell, called actin. The integrins are like small machines. Imagine grappling hooks that you release until they get caught somewhere and then you can pull yourself towards that point. And if the hook does not latch on to something, it is reeled back in," says Pontus Nordenfelt.
The fact that the integrins redirect themselves and move in the same direction is important in order for the cell to turn. However, it is not entirely clear whether it is only the integrins that are facing the right direction that become active, or if the cell is able to redirect the integrins to make them point in the same direction.
Studying the integrins in this way required experts from several different fields. The researchers needed to develop new technologies to be able to see the molecules; among other things, they developed a new microscopic technique that allows you to see the orientation of integrins during the cell's movement in colour images. The[PN1] researchers also used super-resolution technology, which won the Nobel Prize in Chemistry in 2014.
In the study, the researchers used the cells in our immune system called T cells, and connective tissue cells known as fibroblasts. The ideas for the project were formed at the Woods Hole Physiology Course in the United States – a boot camp for researchers to which Pontus Nordenfelt was admitted in connection with his postdoc at Harvard. For more than 125 years, Woods Hole has organised a research summer camp for physicists and biologists – and this interdisciplinary environment leads to exciting collaborations. Like this one.
"At the camp one summer, Tim Hunt discovered cyclins, which led to a Nobel Prize. So it's an extremely stimulating environment. We would not have succeeded if it weren't for this interdisciplinary approach," says Pontus Nordenfelt.
In the future, Pontus Nordenfelt wants to use his microscopic technology to film the role of the integrins during infections. How do bacteria manage to stick and not get flushed away from the cells they attach to, and above all, how do they invade our cells?
"The same molecules that the cells of the body use to wander around and recognise things are used by bacteria to attach themselves to our cells and when they want to invade our cells. Therefore, as a next step, I want to increase my understanding of how the infection process is linked to integrins."
Explore further: How cells move
Pontus Nordenfelt et al. Direction of actin flow dictates integrin LFA-1 orientation during leukocyte migration, Nature Communications (2017). DOI: 10.1038/s41467-017-01848-y