Researchers at the Howard Hughes Medical Institute at The Rockefeller University have isolated stem cells from the skin of a mouse, and showed, for the first time, that an individual stem cell can renew itself in the laboratory and then be used in grafts to produce skin, hair and oil glands.
The study, published in the September 3 issue of the journal Cell, not only demonstrates for the first time the multipotent power of these stem cells, but also holds promise for possible future application of these techniques for the treatment of human skin and hair conditions, says the study's lead investigator, Elaine Fuchs, Ph.D., professor and head of the Laboratory of Mammalian Cell Biology and Development at Rockefeller and an investigator at HHMI. Fuchs also is a member of the Robert and Harriet Heilbrunn Center for Stem Cell Research at Rockefeller.
"This is first work that indicates a single skin stem cell can generate both epidermis and hair, even after propagation in the lab," Fuchs says. "The potential of these stem cells is very exciting."
And in the future, she says, it may be possible to test if human skin cells can also be pushed to grow into other epithelial cells, such as eye cornea or tooth enamel, or even different types of tissues. "My interest has always been to understand biology with an eye toward eventual clinical applications," Fuchs says. "So far, this study has provided some of the answers that we will need to make this possible."
One possible application for the findings is to see if these methods can now be adapted to isolate human hair stem cells for developing future treatments for baldness, she says. In the present study, the Fuchs' team of researchers were able to isolate these stem cells from normal mice, graft them on to the backs of hairless mice, and generate luxuriant hair growth, as well as new glands to oil the hair and fresh skin.
In contrast to recent methods published earlier this year by Fuchs's Rockefeller team and George Cotsarelis's group at the University of Pennsylvania, this new methodology for isolating skin stem cells does not require genetic manipulation. "This opens the door for applying this method for isolating human cells," Fuchs explains.
The findings represent a culmination of years of work in the Fuchs lab on the science of hair and skin growth. This path of discovery has seen many hallmarks of progress, including the creation of transgenic mice with superthick hair growth, the identification of signals that are necessary to make hairs grow, and the earlier isolation and characterization of cells from a region of the hair follicle that researchers in the field thought might be the home of these stem cells.
Because they are so powerful, and so few in number, stem cells are used sparingly by the body and are tucked away in protected places. In the skin, cells suspected of having "stemness" because they divided infrequently were found by researchers to reside in a tiny bulge halfway up the side of a hair follicle shaft.
Earlier this year, researchers in the Fuchs lab reported in the journal Science a method to tag these "slow cycling" cells with a fluorescent marker and watched them travel out of the niche and move down to the bulb of the hair follicle to form new hair or move up to create new skin epidermis, lending more evidence to the idea that these were stem cells. But the researchers didn't know if hair and skin arose from one master cell -- a "multipotent" stem cell that can morph into a number of tissue types -- or from two populations of "unipotent" stem cells that are destined to be a single tissue.
"There has been increasing evidence that there are cells within this compartment that have the capacity to regenerate epidermis in wounding, and to regenerate hair follicles in the normal hair cycle, but it hasn't been clear whether this was due to the action of one stem cell or a bag of different cells," Fuchs says.
In the current scientific paper, the Fuchs team reports on a new system to isolate these cells that avoids the need for genetic manipulations of the mice, and hence may make it applicable in the future to isolate and study human skin stem cells. The different strategy was developed by Rockefeller University postdoctoral research fellows Cedric Blanpain, M.D., Ph.D., and William Lowry, Ph.D. Both are co-first authors of the Cell study. An animal specialist, Lisa Polack, and a graduate student, Andrea Geoghegan, also contributed to the findings.
"We found that the surface of the skin stem cells was different than the other cells of the skin, enabling us to use two different antibodies to sort them out from the other skin cells," says Lowry. "No one had been able to isolate stem cells from the hair follicle in this way before."
Placed in a nourishing culture, the cells began to "self-renew," or replicate themselves. The researchers realized that once these quiescent cells were out of the niche they were free to divide. Further experimentation led to the identification of two growth factors, known as Bmp6 and FGF18, which are expressed specifically in the bulge and keep the stem cells from dividing in the test tube. "In the niche, these factors might help to keep stem cells in a holding pattern -- an environment that inhibits growth -- and that is why they have been recognized as slow cycling," says Lowry.
After expanding an isolated stem cell clone several million times, the researchers grafted the cells on to the back of a mouse that had no hair, and demonstrated that the grafted cells, all derived from a single parent stem cell, made new hair, skin and sebaceous glands, which excrete oil to lubricate the hair.
But the team wasn't quite finished. They used microarray gene expression to determine if the genes expressed by their stem cells were also expressed by other known stem cell types -- blood, embryonic and neuronal stem cells.
"We have found more than 50 genes that are turned on by all the stem cells that our group and other groups have analyzed so far," says Blanpain. "These genes are likely to represent stemness -- the ability to maintain themselves as well as to differentiate -- and that is very interesting because it suggests that different stem cells of the body have certain similarities."
Because the same cell markers used in the mice experiment are thought to be found in human follicle stem cells, Fuchs hopes that similar techniques can be used to isolate human skin stem cells. If successful, the human cells will then be expanded in the lab, and grafted on to mice engineered not to reject the cells, to see if new hair and other epidermal tissue will grow.
As part of the Robert and Harriet Heilbrunn Center for Stem Cell Research that was established in August 2004 at Rockefeller, Fuchs' laboratory is among the six on Rockefeller University's campus that now conduct basic research with embryonic, neuronal and skin stem cells derived from mice, laboratory cultures of human adult skin stem cells and human embryonic stem cells, from both National Institutes of Health Registry and non-Registry cell lines. For more information, visit: http://www.rockefeller.edu/pubinfo/080304.php
The research was supported, in part, by the Howard Hughes Medical Institute and by grants from the National Institutes of Health.
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