Hair follicle stem cells (HFSCs) lacking the protein FOXC1 spend less time in quiescence, leading to markedly shorter resting periods between hair cycles, with consequences for HFSC niches, or bulges. The HFSCs can retain only one old bulge in their hair follicles, while normal stem cells can keep up to four. Ultimately, diminished HFSC niches result in premature graying and sparser coats. [The Laboratory of Mammalian Cell Biology and Development at Rockefeller University/PNAS]
Hair follicle stem cells (HFSCs) lacking the protein FOXC1 spend less time in quiescence, leading to markedly shorter resting periods between hair cycles, with consequences for HFSC niches, or bulges. The HFSCs can retain only one old bulge in their hair follicles, while normal stem cells can keep up to four. Ultimately, diminished HFSC niches result in premature graying and sparser coats. [The Laboratory of Mammalian Cell Biology and Development at Rockefeller University/PNAS]

Many adult stem cells seem to pace themselves as though they need to conserve their regenerative powers for the long haul. But whether these stem cells really need to alternate between periods of busyness and rest, or quiescence, remains an unsettled question.

To shed light on the question, scientists at Rockefeller University effectively took the brakes off stem cells of a particular kind, hair follicle stem cells (HFSCs). Alas, experiments in mice showed that supercharged stem cells did not give rise to richer, fuller coats of hair. Instead, coats grew grayer prematurely. Even worse, the coats became sparser.

These results appeared February 24 in the Proceedings of the National Academy of Sciences (PNAS), in an article entitled, “FOXC1 Maintains the Hair Follicle Stem Cell Niche and Governs Stem Cell Quiescence to Preserve Long-Term Tissue-Regenerating Potential.” FOXC1 refers to Forkhead box C1, a transcription factor expressed in HFSCs. These cells reside a niche called the bulge.

FOXC1-deficient mice were created by knocking out, or “conditionally ablating,” the gene that produces this protein. This intervention revealed that FOXC1 is involved not only in HFSC activity, but also bulge maintenance.

“FOXC1-deficient HFSCs spend less time in quiescence, leading to markedly shortened resting periods between hair cycles,” wrote the authors of the PNAS article. “The enhanced hair cycling accelerates HFSC expenditure, and impacts hair regeneration in aging mice. Interestingly, although FOXC1-deficient HFs can still form a new bulge that houses HFSCs for the next hair cycle, the older bulge is left unanchored. As the new hair emerges, the entire old bulge, including its reserve HFSCs and SC-inhibitory inner cell layer, is lost.”

Essentially, the knockout stem cells enter an overactive state in which they cannot establish quiescence adequately. Also, in the absence of FOXC1, hair follicles always had only one hair despite having made new hairs seven times. This is because these hair follicles could not retain their old bulges, though they generated a new bulge without a problem.

The Rockefeller University researchers attributed these changes to a two-part mechanism—first, a marked increase in cell cycle-associated transcripts upon FOXC1 ablation, and second, a downstream reduction in E-cadherin–mediated inter-SC adhesion.

“As the stem cells started proliferating more, they became less able to stick together,” the authors continued. “As a result, their old bulges did not stay properly tethered to the hair follicle when the newly growing hair pushed past it. And since the bulge emits quiescence signals, its loss activated the remaining stem cells even faster.”

While the hair follicle stem cells of FOXC1-deficient mice produce hairs at a relatively breakneck pace, this profligate growth seems to wear them out. Older knockout mice had sparser, greyer coats, and they could not regenerate their fur as quickly as their normal age-matched or younger peers. A similar phenomenon has been described in mouse hematopoietic stem cells, which give rise to blood cells; those stem cells that are more active in young animals appear to become exhausted as the animals grow older.

“Hair follicle stem cells influence the behavior of melanocyte stem cells, which co-inhabit the bulge niche,” explained Elaine Fuchs, Ph.D., the senior author of the PNAS study. “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.”

Not much is known about naturally occurring hair loss with age, but these balding knockout mice may provide a model to study it. Also, the mice may reveal mechanisms of more general interest.

“We thought initially that the key to hair growth might be the fountain of youth,” noted Dr. Fuchs. “But the mice's hair coat surprisingly thinned and greyed precociously.”