Size Is Important for the Functionality of Stem Cells

In a study published today in Science Advances, MIT biologists addressed an age-old question on why cells control their size, and reported that cellular enlargement drives a decline in the function of stem cells. The team found that blood stem cells lose their ability to perform their normal function—replenishing the body’s blood cells—as they grow larger. However, when the cells were restored to their usual size, they behaved normally again.

The researchers also found that blood stem cells tend to enlarge as they age. Their study shows that this enlargement contributes to stem cell decline during aging. “We have discovered cellular enlargement as a new aging factor in vivo, and now we can explore if we can treat cellular enlargement to delay aging and aging-related diseases,” says Jette Lengefeld, lead author of the study.

It has been known since the 1960s that human cells grown in a lab dish enlarge as they become senescent. Every time a cell divides, it can encounter DNA damage. When this happens, division is halted to repair the damage. During each of these delays, the cell grows slightly larger. Many scientists believed that this enlargement was simply a side effect of aging, but the team began to investigate the possibility that large cell size drives age-related losses of function.

To study how size affects these blood stem cells, the researchers damaged their DNA, leading to an increase in their size. They then compared these enlarged cells to other cells that also experienced DNA damage but were prevented from increasing in size using rapamycin.

After the treatment, the researchers measured the functionality of these two groups of stem cells by injecting them into mice that had their own blood stem cells eliminated. This allowed the researchers to determine whether the transplanted stem cells were able to repopulate the mouse’s blood cells. They found that the DNA-damaged and enlarged stem cells were unable to produce new blood cells. However, the DNA-damaged stem cells that were kept small were still able to produce new blood cells.

In another experiment, the researchers used a genetic mutation to reduce the size of naturally occurring large stem cells that they found in older mice. They showed that if they induced those large stem cells to become small again, the cells regained their regenerative potential and behaved like younger stem cells. “This is striking evidence supporting the model that size is important for functionality of stem cells,” Lengefeld says. “When we damage the stem cells’ DNA but keep them small during the damage, they retain their functionality. And if we reduce the size of large stem cells, we can restore their function.”