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GOING GRAYDNA damage causes hair follicle stem cells to stop renewing themselves, leading to gray hair, a new study shows. Although these two mice are the same age, only the mouse on the right was exposed to DNA-damaging X-rays.Inomata et al./Cell 2009

Gray hair may be a mark of distinction in some circles, but it’s also a sign of a depleted stem cell population. DNA damage causes stem cells that produce hair-color cells in mice to lose their “stemness,” leaving brown hair gray, a report in the June 12 Cell shows. The results suggest a new way stem cell populations can be depleted as cells accumulate DNA damage over time.

The new study “opens up a new paradigm for how we’re going to study stem cell aging in many systems,” comments Kevin Mills of the Jackson Laboratory in Bar Harbor, Maine. The report “fills in what’s been a hole in our understanding of stem cell biology.”

Colorful locks depend on a group of special cells in hair follicles called melanocyte stem cells. Each of these cells divides into two cells: One that replaces itself and another that differentiates into a pigment-producing daughter cell called a melanocyte, which imbues hair with its browns, reds and blacks. Earlier research has suggested that the depletion of these stem cells was to blame for grayness. But how exactly these stem cells disappeared was mysterious. With no more stem cells around to produce melanocytes, hair turns gray.

Emi Nishimura at Tokyo Medical and Dental University in Japan and her colleagues tracked the fate of these stem cells and grayness in mice exposed to DNA-damaging radiation. The exposure level was fairly high, intended to magnify the effects of DNA damage that cells gradually accumulate with age.

Mice typically begin to go gray when they are 1 year to 1½ years old, after about 65 percent of their life, Nishimura says. But following exposure to high doses of radiation, hair on mice as young as 7 to 8 weeks grew in gray, while control mice remained brown, the team found. Other DNA-damaging agents, including hydrogen peroxide, had the same graying effect.

The team next looked at the stem cells in the hair follicles during this graying process. Researchers usually think of two ways stem cells stop working, say Paul Hasty, a geneticist at the University of Texas Health Science Center in San Antonio. The stem cells either die or stop dividing, he says. “But for these melanocyte stem cells, that’s not what happens.”

Instead, the DNA damage causes them to lose their “stemness,” the new report shows. Once the cells have racked up enough DNA damage, they become melanocytes and lose the ability to replace themselves or to replenish melanocyte cell populations. Once the melanocytes die, the hair is left with no pigment-producing cells.

“What’s really unexpected is that the cells differentiate in response to DNA damage,” instead of dying or halting division, Mills says. This irreversible pathway might be going on in stem cells in other tissues like the brain or blood, he notes. Figuring out the details of how these cells lose their “stemness” may ultimately lead to new ways to stave off stem cell depletion. “If you can modulate the stemness checkpoint, you can influence the activity of these stem cells,” Mills says.

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