Commentary

We know that, during aging, hair thinning and hair loss are prominent. However, the mechanism that makes this happen is yet a little unclear. This very interesting article shows that the hair follicle stem cell aging causes the stepwise miniaturization of hair follicles and eventual hair loss in wild-type mice and also in humans. This study revealed, then, that the DNA damage response in the hair follicle stem cells causes proteolysis of type XVII collagen, which is a critical molecule for its maintenance. This initial research may be the first step into a larger aging process prevention.

Introduction

During aging, some organs suffer miniaturization, and their functions and regenerative capability decline gradually. Histologically, tissue atrophy and fibrosis are noticed in many aged organs. However, the exact mechanisms for this functional and architectural decline are yet unknown. Various theories try to explain the organismal aging process, but not from the viewpoint of cellular and tissue dynamics. We know in most mammalian organs, the stem cell systems sustain cellular and tissue turnover, 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 a clear understanding of the mechanisms of the aging process in tissues and organs.

The hair follicle is an epithelial mini-organ of the skin that sustains cyclic hair regrowth over repeated hair cycles. Hair thinning is one of the most featured signs of senescence in many long-lived mammals. The authors studied and described the mechanism for the aging of the epithelial mini-organ. The miniaturization of hair follicles has long been considered to be a specific key phenomenon for male-pattern baldness, as androgenic alopecia, but not for hair follicle aging. This study showed that hair follicles do miniaturize and often disappear from the skin during aging both in mice and humans, regardless of sex.

Likewise, aged hair follicle stem cells are cyclically eliminated from the skin through terminal epidermal differentiation, thereby shrinking the hair follicle. The aging process can be recapitulated by Col17a1 deficiency and prevented by the forced maintenance of this transmembrane protein in the hair follicle stem cells.

Materials and Methods

The authors employed in vivo stem cell fate tracing in mice during physiological aging and searched for possible connections between the cell fate of aged hair follicle stem cells and the stepwise miniaturization and loss of hair follicles. First, the study combined the gene expression profiling of young versus aged hair follicle stem cells and conditional knockout or maintenance of gene expression in hair follicle stem cells in mice. Then, the authors defined the early events and molecules that connect the hair follicle cycling, the hair follicle stem cell aging, and, finally, the dynamic hair follicle aging processes, which are characterized by the stepwise miniaturization of the hair follicles.

Results

The analysis of the hair follicle stem cells during aging revealed that organ aging is primed by the sustained DNA damage response against DNA damage that accumulates in renewing stem cells along time. This is tightly linked to intrinsic genomic instability in stem cells to epithelial organ aging.

Besides, the study found that the stem cell aging process results from the proteolysis of type XVII Collagen (COL17A1/BP180) by neutrophil elastase in response to DNA damage in hair follicle stem cells, and the commitment of the stem cells to epidermal differentiation. Terminal differentiation of hair follicle stem cells into epidermal keratinocytes leads to hair follicle miniaturization, enabling the removal of damaged stem cells as shed corneocytes from the skin surface. The fate of aged hair follicle stem cells withdraws their commitment to follicular differentiation to grow new hair. Finally, hair follicle aging can be recapitulated by the COL17A1 deficiency and prevented by the forced maintenance of this protein in the hair follicle stem cells. Therefore, these results reveal that the COL17A1 is the protein that orchestrates the stem cell–centric aging program of the epithelial mini-organ.

Conclusion

This study used in vivo stem cell fate tracing of hair follicle stem cells to demonstrate its essential role in the induction of aging-associated hair thinning. Plus, the authors identified an organ aging program that is driven by the transepidermal elimination of aged hair follicle stem cells through the depletion of COL17A1 via DNA damage–induced protease expression and terminal epidermal differentiation. The dynamic hair follicle aging program is a good model of organ and tissue miniaturization and functional decline, frequently observed in many different organs. This article reveals a new paradigm that can potentially open new avenues for the development of anti-aging strategies and to prevent and treat diseases associated with the aging process.

Rerefence

H.MatsumaraHair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis J Eur Acad Dermatol Venereo. 2018 Jan;32(1):11-22