Stem cells enable normal cell homeostasis, but they also exist in a quiescent state, ready to proliferate and differentiate after tissue damage. Now, two studies reveal features of stem cells in the hair follicle, an epithelial mini-organ of the skin that is responsible for hair growth and recycling (see the Perspective by Chuong and Lei). Wang et al. found that the Foxc1 transcription factor is induced in activated hair follicle stem cells, which in turn promote Nfatc1 and BMP signaling, to reinforce quiescence. Matsumura et al. analyzed hair follicle stem cells during aging. They identified type XVII collagen (COL17A1) as key to hair thinning. DNA damage-induced depletion of COL17A1 triggered cell differentiation resulting in the shedding of epidermal keratinocytes from the skin surface. These changes then caused hair follicle shrinkage and hair loss.

Structured Abstract

INTRODUCTION During aging, most organs in mammals become smaller (miniaturize) or thinner, and their functions and regenerative capability also decline. Histologically, tissue atrophy and fibrosis are observed in many aged organs. Yet the exact mechanisms for the architectural and functional decline are unknown. Indeed, areas that are as yet underexplored include the dynamics of the constituent cells and their cellular fate, as well as determination of whether aged or damaged cells accumulate or are eliminated in tissues and organs during the aging process. Organismal aging has been explained by various theories—such as reactive oxygen species, cellular senescence, telomere erosion, and altered metabolism—but not from the viewpoint of cellular and tissue dynamics. Stem cell systems sustain cellular and tissue turnover in most mammalian organs, but it has been difficult to experimentally test the precise fate of somatic stem cells, the cellular pool for tissues and organs. This has limited our understanding of the mechanisms of aging of tissues and organs and the existence of an aging program in mammalian organs. The hair follicle (HF) is an epithelial mini-organ of the skin that sustains cyclic hair regrowth over repeated hair cycles. Hair thinning (senescent baldness) is one of the most typical signs of aging in many long-lived mammals and is often prematurely induced by genomic instability, as in progeroid syndromes. We studied the mechanism for aging of the epithelial mini-organ.

RATIONALE Miniaturization of HFs has long been believed to be a specific key phenomenon for male-pattern baldness (androgenic alopecia) but not for HF aging. Our study revealed that mammalian HFs do miniaturize and often disappear from the skin during aging both in mice and humans, regardless of sex. We employed in vivo stem cell fate tracing in mice during physiological aging and searched for possible links between the cell fate of aged HF stem cells (HFSCs) and the stepwise miniaturization and loss of HFs. Combining gene expression profiling of young versus aged HFSCs and conditional knockout or maintenance of gene expression in HFSCs in mice, we defined the early events and molecules that connect HF cycling, HFSC aging, and the dynamic HF aging processes, which are characterized by the stepwise miniaturization of HFs.

RESULT The fate analysis of HFSCs during aging revealed that organ aging is primed by the sustained DNA damage response against DNA damage that accumulates in renewing stem cells during aging. This now tightly links intrinsic genomic instability in stem cells to epithelial organ aging. Further, we found that stem cell aging results from proteolysis of type XVII Collagen (COL17A1/BP180) by neutrophil elastase in response to DNA damage in HFSCs and the commitment of stem cells to epidermal differentiation. Terminal differentiation of HFSCs into epidermal keratinocytes drives HF miniaturization and enables the elimination of damaged stem cells as shed corneocytes from the skin surface. The fate of aged HFSCs abrogate their commitment to follicular differentiation to grow hair. Finally, HF aging can be recapitulated by Col17a1 deficiency and can be prevented by the forced maintenance of COL17A1 in HFSCs. This demonstrates that COL17A1 in HFSCs orchestrates the stem cell–centric aging program of the epithelial mini-organ.