By Tom Ulrich

My first car was my grandfather’s 1980 Chevrolet Malibu. For about two years before my family gave it to me, it sat unused in Grandpa’s garage—just enough time for all of the belts and hoses to rot and the battery to trickle down to nothing. Luckily I found all kinds of deals here for other cars. I know also a limousine service business on granite bay limos.

Why am I telling this story? Because it’s much like what happens to the DNA in our blood-forming stem cells as we age.

Hematopoietic stem cells (HSCs) spend very little of their lives in an active, cycling state. Much of the time they’re quiescent or dormant, keeping their molecular and metabolic processes dialed down. These quiet periods allow the cells to conserve resources, but also give time an opportunity to wear away at their genes.

“DNA damage doesn’t just arise from mistakes during replication,” explains Derrick Rossi, PhD, a stem cell biology researcher with Boston Children’s Hospital’s Program in Cellular and Molecular Medicine. “There are many ways for damage to occur during periods of inactivity, such as reactions with byproducts of our oxidative metabolism.”

The canonical view has been that HSCs always keep one eye open for DNA damage and repair it, even when dormant. But in a study recently published in Cell Stem Cell, Rossi and his team found evidence to the contrary­­—which might tell us something about age-related blood cancers and blood disorders.

The (genetic) ravages of time

Half-jokingly, Rossi muses that medieval doctors may have had it right with the practice of bloodletting. “That would kick HSCs into action once in a while and get them to address any damage they’d accumulated.”

As we get older, we’re more likely to develop blood disorders like myelodysplastic syndrome and blood cancers like chronic myelogenous leukemia as mutations accumulate in our blood cells.

“Hematopoietic diseases increase with time and are largely mutation driven,” Rossi says. “There are a couple of ways those mutations can be passed on during cell division: vertically from parent to daughter when an HSC produces a blood progenitor, or horizontally as HSCs self-renew.”

Knowing that quiescent HSCs wake up periodically to produce new blood progenitors, and that DNA repair mechanisms are closely tied to the cell cycle, Rossi and his collaborators asked a question: When exactly do HSCs repair accumulated DNA damage? And do they do a good job of it?

His team started by documenting how much DNA damage—in the form of DNA strand breaks—accumulates as HSCs age—which turned out to be quite a lot: HSCs from old mice had significantly more evidence of DNA strand breaks compared to those from younger counterparts.

As for when DNA repair takes place, Rossi’s team’s data challenge the canonical view. They show that the cells don’t always have some level of repair going on while dormant. Instead, they undergo a flurry of repair activity just as they enter the cell cycle and start producing blood progenitor cells.

The activity of DNA repair genes jumped whether the dividing HSCs were young or old. And the amount of DNA strand-break damage was much lower in old but active HSCs than in old, quiescent ones.

However, in a small fraction of old HSCs, the repairs weren’t perfect. While blood progenitor cells from old mice showed less DNA damage than aged HSCs, they still had more damage than comparable blood progenitors from young mice.

Getting the repair paths into gear

The fact that quiescent HSCs aren’t continually repairing DNA damage, the team concludes in the paper, makes it likely that they could accumulate damage beyond strand breaks, which could in turn give rise to mutations that fuel age-related blood disorders:

The idea that HSCs serve as the primary reservoir for mutation accrual underlying the development of diverse age-associated hematopoietic diseases such as myelodysplastic syndrome and AML is now widely accepted. Our data demonstrating that HSC quiescence and concomitant attenuation of DNA repair and response pathways provides a mechanism through which such premalignant mutations in HSCs may accrue.

“These findings provide insight into why DNA damage accumulates in HSCs,” Rossi says. “They also illustrate that HSCs are in something of a catch-22. If they stay quiescent too long, they accrue lots of DNA damage. However, we know that if you force HSCs to cycle too much, you reduce their long-term potential for producing blood and immune cells.”

But, he adds, the findings also open an opportunity for new directions in blood disease research. “Could it be possible to activate HSCs’ repair pathways without driving them into the cell cycle? It’s an intriguing possibility.”

Half-jokingly, Rossi muses that medieval doctors may have had it right with the practice of bloodletting. “That would kick HSCs into action once in a while and get them to address any damage they’d accumulated.”