Cell migration: a tug-of-war inside your body

Original article: Physical forces during collective cell migration

If you ever played tug-of-war in elementary school, you might remember that it isn’t the friendliest game. People fall over, hands get burned from holding on to the rope, and knees get scraped from falling on the ground. Although victory can be sweet, the injuries that come with it may make you never want to play the game again. Perhaps surprisingly, there is a similar ‘’tug-of-war” happening inside your body, as individual cells move around from one place to another in a process called cell migration. What’s more, this microscopic tug-of-war may help to heal those scrapes and bruises that happened in elementary school, and those that happen in your everyday life.

A single cell moves by detaching and reattaching from the substrate, or the surface it is on, as the cell  expands and contracts. This movement exerts forces on the substrate. (These forces can actually be measured directly –  this is the topic of a previous softbites post.) When many cells move together in a “cell sheet”,  their motion becomes more complicated. Not only do cells push and pull on the substrate, but they also push and pull on the cells that surround them.  In today’s study, Xavier Trepat and colleagues show that there is a “tug-of-war” between cells that causes them to migrate.

Previously, it was thought that only the cells at the very front of the mass of migrating cell, or the leading edge of the cell sheet, exert forces on the substrate. According to this picture, most of the cells get passively pulled along by the leading edge, and neither push nor pull on the substrate. By measuring the forces the cells exert on the substrate, Trepat and his colleagues discovered that, in fact, all of the cells are involved in pushing the cell sheet forward.

The researchers measured the forces in a moving sheet of cells, taken from canine kidneys, growing on a gel substrate using a technique called traction force microscopy. The first step of this technique is to track the displacements of different points within the substrate as the cells move. Then, the mechanical properties of the gel are used to calculate the forces on the substrate generated by this motion. The researchers mapped the value of these forces using different colors, with red and blue representing very strong forces and black representing zero force. They first looked at what happened at the leading edge of the cell sheet, as in Figure 1.

Figure 1. a. Image of the cell sheet, in which individual cells are outlined in white. The field of view is 700 microns by 700 microns. b. The forces that the cells exert perpendicular to the leading edge of the cell sheet. c. The forces that the cells exert parallel to the edge of the cell sheet. Bright red and blue colors indicate strong forces (up to 100 Pa of stress), while black color indicates low forces. (Images adapted from the original article.) The cell sheet’s expansion was recorded in a video as well.

The researchers separated the normal forces (Figure 1b) — those exerted by the cells perpendicular to the leading edge of the cell sheet, or in the direction of the cells’ motion — from the forces exerted parallel to the leading edge of the cell sheet (Figure 1c). The bright red and blue colors in Figure 1 show that cells well inside the cell sheet exert forces on the substrate. From this, they hypothesized that instead of having “follower” and “leader” cells, all the cells contribute into pushing and pulling the cell sheet as they move.

The researchers then looked at larger areas of the cell sheet, such as that  shown in Figure 2. The bright colors near the edges correspond to strong forces,  while the black spots show that the forces in the center of the cell sheet are weaker. This suggests that the cell sheet “tugs” both to the right and the left as it expands. As the cells exert forces on the substrate, they exert forces on each other. The cells pulling to the right and the left are similar to two teams pulling a rope in a game of tug of war. The sheet of cells is like a rope that grows in the direction of the tugging of the cells.

Figure 2. Forces exerted by a larger piece of the cell sheet. Bright red indicates strong positive forces and blue indicates strong negative forces, while black indicates low forces. The scale bar on the bottom right is 200 micrometers.  (Image adapted from the original article.)

Next, the researchers wanted to understand how being tugged on by its neighbors affects the motion of individual cells: does the tug of war consistently pull a cell in a particular direction? Or is the cell equally likely to be pulled in any direction?  To answer this question, Trepat and colleagues measured the average force exerted on a cell by its neighbors, as a function of the distance of that cell from the edge of the sheet. If each cell was moving independently, the average normal force inside the sheet would be zero – on average, no cell would be pushing or pulling any other cell to a specific direction. Instead, as shown in Figure 3, the average force was not zero, and was actually higher for distances farther from the sheet’s leading edge. In other words, the cell sheet is expanding from the inside more than it’s being pulled from the edge.

Figure 3. The average normal force exerted on a cell by its neighbors, \sigma_{xx}, is higher farther from the leading edge of the cell sheet. (Figure adapted from the original article.)

Each individual cell crawling on a substrate has little effect on its surroundings, but many cells acting together can exert forces on each other to guide the collective in a particular direction. As cells replicate, such as in a healing wound, this guiding helps the cells expand in directions where there is space to be filled. This study by Trepat and colleagues reveals for the first time the tug-of-war that allows the tissues in our bodies to grow and heal.

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