Androgen Receptor Accelerates Premature Senescence of Human Dermal Papilla Cells in Association with DNA Damage

Yi-Chien Yang,Hung-Chun Fu,Kuo-Ting Wei,Hong-Yo Kang,Ko-En Huang,Ching-Yuan Wu,Arianna L Kim

doi:10.1371/journal.pone.0079434

Yi-Chien Yang, Hung-Chun Fu + Show 5 more

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https://doi.org/10.1371/journal.pone.0079434

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Abstract

The dermal papilla, located in the hair follicle, expresses androgen receptor and plays an important role in hair growth. Androgen/Androgen receptor actions have been implicated in the pathogenesis of androgenetic alopecia, but the exact mechanism is not well known. Recent studies suggest that balding dermal papilla cells exhibit premature senescence, upregulation of p16INK4a, and nuclear expression of DNA damage markers. To investigate whether androgen/AR signaling influences the premature senescence of dermal papilla cells, we first compared frontal scalp dermal papilla cells of androgenetic alopecia patients with matched normal controls and observed that premature senescence is more prominent in the dermal papilla cells of androgenetic alopecia patients. Exposure of androgen induced premature senescence in dermal papilla cells from non-balding frontal and transitional zone of balding scalp follicles but not in beard follicles. Overexpression of the AR promoted androgen-induced premature senescence in association with p16INK4a upregulation, whereas knockdown of the androgen receptor diminished the effects of androgen. An analysis of γ-H2AX expression in response to androgen/androgen receptor signaling suggested that DNA damage contributes to androgen/androgen receptor-accelerated premature senescence. These results define androgen/androgen receptor signaling as an accelerator of premature senescence in dermal papilla cells and suggest that the androgen/androgen receptor-mediated DNA damage-p16INK4a axis is a potential therapeutic target in the treatment of androgenetic alopecia.

Highlights

Androgenetic alopecia (AGA) is an androgen-mediated disorder that causes hair thinning in a defined pattern [1,2]
Balding dermal papilla cells (DPCs) isolated from AGA patients showed broader and polygon-shaped morphology (Fig. 1B) in contrast with the elongated, fibroblast-like appearance of DPCs isolated from the normal individuals (Fig. 1A)
While the cell doubling time was variable among the same passage of balding DPCs from different AGA patients, the balding DPCs have relative longer cell doubling time compared to non-balding DPCs (Fig. 1E)

Summary

Introduction

Androgenetic alopecia (AGA) is an androgen-mediated disorder that causes hair thinning in a defined pattern [1,2]. In dermal papilla cells (DPCs), the major circulating androgen, testosterone (T), can be locally metabolized to dihydrotestosterone (DHT) by steroid 5a-reductase. According to the observation that male subjects with genetic deficiency of type 2 5a-reductase do not develop scalp hair loss [5], DHT has been suggested to be a major determinant in the pathophysiology of AGA in men. In AGA, DPCs from androgen-sensitive frontal scalp contain more AR and steroid 5a-reductase than those from androgen-insensitive occipital scalp [6]. AGA is characterized by miniaturization of hair follicles in the androgen-sensitive frontal scalp. In clinical observations, blocking the conversion of T to DHT with finasteride, a 5a reductase inhibitor, does not reverse miniaturized follicles to thick hair fibers in advanced AGA [10], suggesting that androgens/AR might irreversibly cause the damage of hair follicles

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