In their research, published in PNAS, Elaine Fuchs, professor at Rockefeller University, and Kenneth Lay, a graduate student in her lab, identify Forkhead box C1 (FOXC1) as a key transcriptional regulator of hair follicle stem cell (HFSC) activity and bulge maintenance.
They found that loss of FOXC1 reduces the threshold for HFSC activation, causing excessive HFSC usage and dramatically shortens periods between hair growth cycles.
Stem cells residing in hair follicles are held in an inactive state, a bulge, for long periods of time and while in this quiescent state, they don't reproduce until they receive signals from their surroundings that it's time to regenerate.
Usually the stem cells create a new bulge along with the new hair, while ensuring that the old bulge and the old hair stay put in the hair follicle.
Only the new bulge can make another new hair, but the old bulge is kept in place to maintain a thick and lush coat.
In order to study this further, the scientists carried out a study in mice, as for them hair follicles can accumulate up to four of these bulges, building on previous work.
"In an earlier study, my lab showed that when mice age, the old fat in their skin produces higher levels of a secreted signal, called BMP," Fuchs says. "This signal acts as a molecular brake on the hair follicle stem cells, causing them to spend much longer times in quiescence."
In this study, Lay identified the stem cell gene that is activated by BMP signalling, and showed that when this gene is missing, the stem cells grow hairs with dramatically shorter intervals.
"We thought initially that the key to hair growth might be the fountain of youth, but the mice's hair coat surprisingly thinned and greyed precociously,” says Fuchs.
When Lay and Fuchs created mice that lack FOXC1, by disabling the gene that produces this protein, they observed that the animals' hair follicle stem cells spent more time growing hairs and less time in quiescence.
Over the course of nine months, while hair follicles from normal mice grew four new hairs, those from the FOXC1 knockout mice had already made new hairs seven times.
"The knockout stem cells enter an overactive state in which they can't establish quiescence adequately," explains Lay.
Because of this over-activity, the hair follicles could not retain their old bulges and could not stay properly tethered to the hair follicle when the newly growing hair pushed past it, meaning only one hair would grow through and hair would lose its thickness.
And since the bulge emits quiescence signals, its loss activated the remaining stem cells even faster, speeding up the cycle.
Though hair had no problem growing, it was more damaging to the hair follicle, and with the absence of FOXC1 producing hairs at such pace, it wears the HFSC out quicker leading to greying and hair loss.
"Hair follicle stem cells influence the behaviour of melanocyte stem cells, which co-inhabit the bulge niche," explains Fuchs.
"Thus, when the numbers of hair follicle stem cells declined with age, so too did the numbers of melanocyte stem cells, resulting in premature greying of whatever hairs were left."
The researchers say that not much is known about naturally occurring hair loss with age, but these balding knockout mice may provide a model to study it.