Few things about growing older are as inevitable and obvious as “going gray,?yet scientists have been unable to explain the precise cause of this usually unwelcome transformation. In a report posted today on the Web site of the journal Science, researchers from Dana-Farber Cancer Institute and Children’s Hospital Boston say they have found the cellular cause of graying hair while investigating the origins of malignant melanoma, the potentially deadly skin cancer.
The
scientists traced the loss of hair color to the gradual dying off of
adult stem cells that form a reservoir that spawns a continuous supply
of new pigment-manufacturing cells, called melanocytes, that give hair
its youthful hues. Not only do the non-specialized stem cells become
depleted, they also progressively make errors, turning into fully
committed pigment cells in the wrong place within the hair follicle,
where they are useless for coloring hair.
The new findings won’t lead to a scientific alternative to hair dyes
any time soon, if ever, even if they do solve a longstanding puzzle
about the underlying mechanism of graying. Of more interest to the
researchers is the pattern of cellular signals that triggers the death
of pigment stem cells, since melanoma is dangerous for the opposite
reason –melanocytes proliferate uncontrollably to form tumors and are
hard to kill with treatment.
“Preventing the graying of hair is not our goal,?emphasizes David E.
Fisher, MD, PhD, director of the Dana-Farber Program in Melanoma, and
senior author of the Science paper. “Our goal is to prevent or treat
melanoma, and to the extent this research is revealing the life cycles
of melanocytes, which are the cells that become cancerous in melanoma,
we would love to identify a signal that would make a melanoma cell stop
growing.?Fisher and the report’s lead author, Emi K. Nishimura, MD, PhD, also of
the melanoma program, are in the Department of Pediatric Oncology at
Children’s Hospital Boston as well as at Dana-Farb
er. The second
author, Scott R. Granter, MD, is a pathologist at Brigham and Women’s
Hospital.
The American Cancer Society expects about 55,100 people to be diagnosed
with melanoma, the most serious form of skin cancer, in 2004, with an
estimated 7,910 deaths. Melanoma can be cured when it is detected and
treated early, but if the lesion penetrates deeply into the skin it is
often fatal. Sun exposure is a major risk factor in the disease, which
has been increasing in the past several decades.
Melanocytes, which manufacture and store the pigment that combines with
hair-making cells called keratinocytes to color the hair, are
specialized cells spawned by colorless melanocyte stem cells. These
cells were discovered by Nishimura in 2002.
A pool of undifferentiated melanocyte stem cells resides in the hair
follicle, and during the hair’s grow-and-rest cycle, the stem cells
give rise to color-making melanocytes that journey to the bottom of the
hair follicle: That is where they tint the keratinocytes with the
person’s characteristic hue.
By studying mice at progressively older intervals, Fisher and his
colleagues discovered that as the rodents aged and their hair began
turning gray, the numbers of stem cells diminished in proportion to the
loss of color. The scientists were surprised to observe that, at the
same time and the same rate, differentiated, pigmented melanocytes were
showing up in the follicle at the location where the stem cells
resided. Since they were in the wrong place, the pigmented cells likely
did nothing to maintain the mice’s hair color.
To see if the cells behaved the same way in humans, the investigators
examined human scalp tissue taken at increasing ages, and determined
that the same pattern occurred.
Since cell survival in general is influenced by an “anti-death?gene
called Bcl2, Fisher’s team analyzed mice lacking this gene. In a
dramatic fashion, the mice lost their melanocyte stem cells shortly
after birth and quickly went gray. It may be that
people who gray
prematurely have mutations that knock out Bcl2 activity, Fisher says.
“This tells us there is a requirement for Bcl2 in normal hair follicle
cycling,?adds Fisher. “So the question is: what in the hair follicle
is signaling the stem cells that is absent when aging occurs and the
stem cells die off? Now we have a much more refined way of dissecting
that signaling pathway in melanoma. Eventually we hope to tap into this
death pathway, thereby using drugs to mimic the aging process, to
successfully treat melanoma.?The team also made mice lacking a gene, MITF that regulates Bcl2. These
mice also went gray, but more gradually than did the mice that had no
Bcl2. The loss of MITF activity, the investigators say, appears to be
implicated in the mistaken differentiation of melanocyte stem cells
that accompanies the stem cells?depletion. MITF, they conclude, seems
to play a crucial role in maintaining the supply of stem cells within
the hair follicle, and graying is the result of “incomplete maintenance
of melanocyte stem cells.?The research was supported by the National Institutes of Health, and
Nishimura received funding from The Shiseido Award in 2002 and The
Charles A. King Trust of Fleet National Bank and The Medical
Foundation.
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Source:
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