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Tracking stem cells
A technique developed in mice follicles may help scientists locate stem cells in humans
Despite all the scientific and political excitement surrounding stem cells, they can be tough targets to find.
Elaine Fuchs, head of Rockefeller’s Laboratory of Mammalian Cell Biology and Development, and Tudorita Tumbar, a Life Sciences Research Foundation postdoctoral fellow in Fuchs’ laboratory, have now devised a system to track and isolate skin stem cells in mice. Their technique could be the first broadly adaptable way to find the master cells that hold the key to regenerative medicine.
Stem cells live in protected pockets of the body called niches, where they divide infrequently to avoid accumulating damaging mutations. Upon injury or in response to normal wear and tear, stem cells are mobilized to leave their niche and divide. Their daughter cells replenish damaged body tissue. Fuchs’ study provides a list of more than 150 genetic factors that distinguish the long-lived, slow cycling stem cells from their short-lived, rapidly dividing daughter cells. Although Fuchs studied mouse skin cells, these genetic factors may prove to apply to stem cells for other body issues — such as those of the heart and pancreas — targeted for regenerative medicine.
“We now have a much better picture of the traits of mouse skin stem cells, and we can use these genetic data to examine whether human skin stem cells possess similar traits to the mouse stem cells,” says Fuchs, who is the university’s Rebecca C. Lancefield Professor and is also a Howard Hughes Medical Institute investigator.
Researchers discovered several years ago that skin niche cells in mice that had been tagged with a chemical marker could travel out of the niche and form new hair or skin. Reasoning that some of these cells were skin stem cells, the Fuchs team developed a system to identify them, isolate them and compare their genetic profile with known stem cells.
The system, dubbed “pulse and chase,” required the development of a genetically altered mouse designed to express a fluorescent protein that causes all skin epithelial cells, including stem cells, to glow green during the “pulse.” By adding drugs to the mouse chow, the researchers could start the “chase,” turning the fluorescent protein off, and watching what happened as rapidly dividing cells slowly lost their glow. At the end of the chase, only the “slow cycling” cells of the skin glowed green.
The slow cycling cells, presumed to be stem cells, glowed for months after the others had stopped. “After one month, we could see that all the remaining very bright green cells, which we predicted to be stem cells, were in the niche,” says Tumbar.
The researchers took the stem cells out of the niche and used microarray technology to obtain the cells’ genetic information. Many of the 150-plus DNA sequences they found code for proteins that are located on the surface of the slow cycling stem cells or are secreted by them. Those proteins are new markers that may help find stem cells in human tissue, the researchers say.
“Previously we knew of just a handful of proteins that distinguish skin stem cells from their progeny, and now we know of more than 100,” says Fuchs. “The laboratory is now working to understand how these proteins define the characteristics of these stem cells, such as their slow cycling properties, their ability to be mobilized to repair skin epidermis in response to wound injuries, and their ability to grow new hair in the normal course of rejuvenation. We are just at the tip of the iceberg.”
The researchers also compared genes found in the skin stem cell niche with those found in blood, brain and embryonic stem cells — and found that 40 percent of the genes expressed in slow cycling skin cells, compared with the genes found in their daughter cells, were also expressed in these other stem cell types.
Fuchs suggests that the skin stem cell model system could hold promise for a variety of medical applications, such as improved regeneration of skin epidermis for burn victims. “And this powerful tool may now help us to identify stem cells in other tissues that undergo extensive rejuvenation, like those in the gut and in cornea. We may even be able to identify and isolate mutated stem cells that lead to certain kinds of cancer,” she says.

December 12, 2003



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