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Stem cells perform
Rockefeller researchers create skin, hair and oil glands from a single adult precursor cell
BY RENEE TWOMBLY
Despite all the buzz surrounding stem cells, researchers have had a hard time actually getting them to do in the lab what they are destined to do in the body: develop into the specialized cells that characterize specific tissues.
Now, in what could be a major leap toward the goal of using stem cells in regenerative medicine,Rockefeller’s Elaine Fuchs has isolated adult stem cells from the skin of a mouse and shown, for the first time, that individual stem cells can renew themselves in the laboratory and then be used in grafts to produce skin, hair and oil glands.
Her lab’s findings, published in the September 3 issue of the journal Cell, are the first demonstrating the multipotent power of these stem cells, and also hint at future applications for the treatment of human skin and hair conditions, says Fuchs.
“This is the 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.”
These results represent the 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 molecular signals required for hairs to grow, and the isolation and characterization of cells from a region of the hair follicle — the “bulge” — that researchers in the field thought might be home to stem cells.
Earlier this year in the journal Science, Fuchs and her colleagues reported a method to tag the slow-growing cells they found in the bulge with a fluorescent marker, and then watched them travel either down to the bulb of the hair follicle to form new hair, or up to the surface to create new skin epidermis. But the researchers didn’t know whether 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 were 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 stem cells,” says Fuchs, who is Rockefeller’s Rebecca C. Lancefield Professor and part of the Robert and Harriet Heilbrunn Center for Stem Cell Research as well as the Howard Hughes Medical Institute.
Fuchs and her team isolated these stem cells from normal mice without using genetic techniques, in contrast to methods published earlier this year by Fuchs’s Rockefeller team and a group at the University of Pennsylvania.“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,” explains William Lowry, a postdoc in Fuchs’s Laboratory of Mammalian Cell Biology and Development, who developed the technique with fellow postdoc Cedric Blanpain. “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 replicate.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 replicating an isolated stem cell clone to produce several million copies of the original cell, the researchers grafted the cells onto the back of a mouse that had no hair.The grafted cells, all derived from the clone, made new hair, skin and sebaceous glands, which excrete oil to lubricate the hair.
If the methods can be adapted to isolate human hair stem cells, a new treatment for baldness could be on the horizon. Because the same cell markers used in the mouse experiment are thought to be found in human follicle stem cells, and because they did not manipulate any genes in order to isolate the cells, Fuchs hopes that her techniques will translate well to human skin stem cells. If successful, the human cells will then be expanded in the lab, and grafted onto mice engineered not to reject the cells, to determine whether new hair and other epidermal tissue will grow.
Human stem cells from skin may even be able to grow into other types of epithelial cells, such as those that comprise the eye cornea or tooth enamel. More broadly, the research may also have implications for understanding stem cells beyond those that reside in the skin.
The research team searched in other types of stem cells for genes that were also active in their skin stem cells.“Our lab and other groups thus far have identified more than 50 genes that are turned on in skin stem cells as well as other tissues’ stem cells,” says Blanpain. “These 50 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.”The group looked at blood and neuronal stem cells as well as embryonic stem cells.
“My interest has always been to understand biology with an eye toward eventual clinical applications. So far, this study has provided some of the answers that we will need to make this possible,” says Fuchs.

October 15, 2004



 

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