On a packed bus, passengers instinctively edge away from the person who has taken up too much space or is acting strangely. Something similar happens in the body's tissues: when a senescent cell, one that has stopped dividing but hasn't died, appears among normal cells, its neighbors begin to crowd it. In a new study, researchers have shown for the first time that this is not just a metaphor: normal cells literally squeeze out the senescent cell, compressing it until it dies. And it doesn't die by accident, but through a programmed pathway: apoptosis.
The authors created cells in which they could switch on the production of progerin, a protein that causes premature aging. These cells were seeded among normal ones at a ratio of 1:50 and observed under a microscope. It turned out that cells with progerin die significantly more often than in the control. But only if they are in close contact with normal neighbors. When such cells were grown alone or next to cells with a disrupted cell adhesion protein E-cadherin, death decreased.
To confirm that the cells really do compress each other, the scientists used traction force microscopy: fluorescent beads were embedded in the elastic substrate on which the cells grew. By the displacement of these beads, one can calculate the forces the cells apply to the surface. It turned out that before the senescent cell died, neighboring normal cells exerted a sustained compressive stress on it. In other words, the neighbors weren't just touching it, they were actively pushing.
What happens inside the senescent cell under such pressure? The scientists found that the signaling pathways JNK and p38-MAPK become activated in it, raising the level of the p53 protein and lowering the level of the p21 protein. p21 normally protects the cell from apoptosis, and its decline makes the cell vulnerable. When the researchers added JNK and p38 inhibitors, the p21 level was partially restored, and the cells survived. This confirms that mechanical compression triggers a signaling cascade that leads to death.
Curiously, not all senescent cells are equally sensitive to being squeezed out. If senescence was caused by a different protein, p16 rather than progerin, the cells did not die under the same conditions and maintained a high level of p21. This suggests that mechanical competition depends on the type of senescence. Perhaps differences in secreted factors (SASP) affect how neighbors recognize and compress the senescent cell.
So the tissue behaves like a community that gets rid of an unwanted member not through the immune system, but through simple physical pressure. This mechanism could become the basis for new approaches in gerontology and regenerative medicine, although clinical application is still a long way off. The next step is to check whether such squeezing works in a living organism, where cells are surrounded by a three-dimensional matrix and immune cells.
Progerin, a mutant form of lamin A, causes progeria, a rare disease in which children age 5–10 times faster than usual. In the experiment, cells with progerin died from compression by neighbors, even though senescent cells are usually resistant to apoptosis.
In the film Blade Runner, replicants are programmed for a short life, and their cells age at an accelerated rate. The mechanism described in the paper resembles a scene where society squeezes out those who are different: normal cells literally press senescent cells out of the tissue.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.