U-M scientists trigger new hair growth in mice

Brief activation of signaling protein stimulates hair follicle growth phase

University of Michigan graduate student David Van Mater knew something strange was going on when he noticed stubble on the shaved skin of experimental mice in his laboratory. Instead of the tumors he had originally expected to see, the mice were growing hair.

Van Mater had stumbled on the discovery that beta-catenin (“bay-tuh-kuh-TEEN-in”), a signaling protein involved in embryonic development and several types of cancer, also triggers changes in adult mouse hair follicles that lead to the growth of new hair.

The discovery by Van Mater and U-M scientists Frank T. Kolligs, M.D., Andrzej A. Dlugosz, M.D., and Eric R., Fearon, M.D., Ph.D., will be published in the May 15 issue of Genes & Development.

“Other researchers have shown that beta-catenin and other genes in the Wnt (“wint”) pathway are important for normal development of hair follicles in embryos and after birth,” says Dlugosz, an associate professor of dermatology in the U-M Comprehensive Cancer Center. “What’s new about our study is the finding that a brief activation of beta-catenin in resting hair follicles could be enough to trigger the complex series of changes it takes to produce a normal hair.”

The original purpose of the research study was to learn how the Wnt signaling pathway and beta-catenin are connected to cancer development, according to Fearon, the Emanual N. Maisel Professor of Oncology in the U-M Cancer Center. “Beta-catenin carries signals from growth factors called Wnts to the cell’s nucleus,” Fearon says. “If beta-catenin expression in the cell isn’t adequately controlled and regulated, it changes normal patterns of gene expression. This can lead to several types of cancer, especially colon cancer.”

The study used genetically altered mice developed in the U-M Transgenic Animal Model Core. By adding a packaged set of genes called a construct to fertilized mouse eggs, U-M researchers created a new strain of transgenic mice with an inducible form of beta-catenin in their skin cells and hair follicles.

Van Mater induced beta-catenin signaling activity by applying a chemical called 4-OHT to shaved areas on the backs of the transgenic mice and matched control mice with normal beta-catenin genes. This chemical turned on the beta-catenin in the skin and follicles of the transgenic mice. The plan was to use 4-OHT to turn on beta-catenin activity in the transgenic mice until skin tumors developed, and then turn off beta-catenin activity to see if the tumors disappeared.

“But we never saw tumors — just massive hyperplastic growth of hair follicle cells,” Van Mater says. The scientists also noticed other skin changes that suggested an exaggerated growth phase of the hair cycle. Dlugosz suggested applying 4-OHT just once, instead of every day, and to do it during the hair follicles’ resting phase or telogen.

“Hair follicles are like a mini-organ in the body,” explains Van Mater, a graduate student in the U-M Medical School’s Medical Scientist Training Program. “Unlike most organs in the adult body, hair follicles go through regular cycles of growth, regression and rest. They are able to regenerate completely during each growth phase. Previous studies had suggested that a Wnt signal might be the switch that drives resting hair follicles into the active growth phase. By treating the transgenic mice with a single application of 4-OHT, we hoped to mimic the effect of a short pulse of Wnt expression in normal mice.”

So Van Mater started over — applying 4-OHT just once to the shaved backs of transgenic mice and normal mice during the telogen phase of the hair cycle. Fifteen days later, the transgenic mice needed another shave, but there were no signs of new hair growth on the control mice.

“Our findings suggest some potential strategies for inducing hair growth, but it is premature to think these results will lead to new approaches for treating common male-pattern baldness,” Dlugosz cautioned. “Many hair follicles in bald and balding men are greatly reduced in size, so merely reactivating hair growth would not produce a normal hair. Also, activation of beta-catenin in the body would need to be tightly regulated, since uncontrolled beta-catenin activity can lead to tumors of hair follicle cells or tumors in other sites, such as the colon, liver or ovary.”

The research was funded by the National Cancer Institute of the National Institutes of Health. Co-author Frank T. Kolligs, M.D., a U-M former post-doctoral scholar working in Fearon’s laboratory, is now at the University of Munich.