Within a structure called the hair follicle bulge, cells with stem cell activity have long been considered a quiescent population, but a paper published this month in Nature Genetics may have turned this theory on its head1. In fact, the hair follicle contains a population of actively cycling, multipotent hair follicle cells that can be identified by the expression of a single protein called Lgr5 (leucine-rich G protein–coupled receptor 5).

Cycling cells in the mouse intestine had recently been shown to express Lgr5, and other studies have discovered that a population of cells in the hair follicle bulge express the protein as well, so Rune Toftgård of the Karolinska Institutet in Stockholm, Sweden, used transgenic mice to characterize the Lgr5-expressing cells in the hair follicle. They discovered that the protein was expressed more widely than expected, especially in the lower bulge and secondary germ layer of telogen (resting) hair follicles and in the outer root sheath area of anagen (growing) hair follicles. Cells expressing Lgr5 were the first to respond to anagen growth signals and, during the growth phase, were present along the length of the follicle. “The trafficking of stem cells along the follicle was a surprise to us,” says Toftgård. “We had to ask: Did the cells in that location retain stem cell function?”

A series of in vivo and in vitro experiments showed that the Lgr5+ cells were indeed able to generate all cell types in a hair follicle. Moreover, progeny of the Lgr5+ cells could be maintained in the hair follicle for over 14 months. Some genetic tricks allowed the researchers to label Lgr5+ cells at specific points during hair follicle growth so they could track the destinations of descendants within the hair follicle. “We needed hard evidence to prove that stem cell function was retained, because the presence of stem cells outside the bulge is a contradictory view,” says Toftgård. Together, the results suggest that Lgr5+ cells are a dynamic population that actively migrate in the hair follicle during the anagen phase and are also able to contribute to permanent parts of the hair follicle. Hedgehog, an important developmental protein, may have a role in maintaining these cells. “The data seem to show that stem cells are not dependent on the bulge niche,” says Toftgård. “Stemness is intrinsic.”

“The exciting thing for me is catching the stem cells in action,” says Denis Headon, a hair follicle development specialist at the University of Manchester, UK. Rather than cycling only occasionally, this work suggests a constant flux of cells, he says, and this knowledge can help researchers pinpoint the function of various stem cell populations within the hair follicle. “The idea that these cells are the ones responding to Hedgehog, which is required for hair follicle activity, would make good sense,” he says. Toftgård wants to look next at how these findings translate to humans, but he acknowledges that this may be difficult because human hair follicle stem cells do not express the same markers as those in mice. However, he can use mice to study the role these cells might play in cancer, he says. “It is likely that these Lgr5+ cells might be the basis of basal cell carcinomas, and now we have the tools to test this genetically.”