The Biology and Genomics of Human Hair Follicles: A Focus on Androgenetic Alopecia

Abstract

Androgenetic alopecia is a highly prevalent condition mainly affecting men. This complex trait is related to aging and genetics; however, multiple other factors, for example, lifestyle, are also involved. Despite its prevalence, the underlying biology of androgenetic alopecia remains elusive, and thus advances in its treatment have been hindered. Herein, we review the functional anatomy of hair follicles and the cell signaling events that play a role in follicle cycling. We also discuss the pathology of androgenetic alopecia and the known molecular mechanisms underlying this condition. Additionally, we describe studies comparing the transcriptional differences in hair follicles between balding and non-balding scalp regions. Given the genetic contribution, we also discuss the most significant risk variants found to be associated with androgenetic alopecia. A more comprehensive understanding of this pathology may be generated through using multi-omics approaches.

Keywords: androgenetic alopecia; genomics; transcriptomics.

Figure 1

Schematic representations of the anatomy of the hair follicle. (A) Four main regions divide the hair follicle: bulb, suprabulb, isthmus, and infundibulum. (B) In a transversal view, the hair follicle appears as a cylinder formed by eight concentric layers forming the outer root sheath (ORS), inner root sheath (IRS), and the hair shaft. The IRS is composed of four layers: companion layer, Henle’s layer, Huxley’s layer, and IRS cuticle. The hair shaft is composed of the medulla, cortex, and hair cuticle.

Figure 2

Key stages of the hair cycle. The hair follicle cycles through three phases: anagen (active regeneration), catagen (apoptotic involution), and telogen (resting phase) throughout life. In the anagen phase, the follicle becomes elongated and acquires an onion-like shape. Secondary hair germ cells (SHG) in the matrix proliferate intensively and differentiate into cells of the inner root sheath and hair shaft. After hair follicle maturation, the regression phase is initiated. Apoptosis of cells of the lower, cycling portion of the hair follicle occurs, bringing the dermal papilla into close proximity to the bulge, a condition that is maintained in the telogen phase. Molecular signaling between stem cells in the bulge (hair follicle stem cells, HFSCs) and the dermal papilla are responsible for the re-entrance into the anagen phase.

Figure 3

Numerous factors that contribute to the pathogenesis of androgenetic alopecia. All factors are interdependent and contribute to the formation of complex feedback loops. Individuals predisposed by inherited genetic mutations depict an increased sensitivity to DHT and a higher activity of 5α-reductase type 2 enzyme, driving downstream transcriptional dysregulations. Furthermore, environmental factors (pollution and UV radiation) and lifestyle-related factors (smoking, exercising, nutrition) potentially trigger epigenetic modifications that affect gene expression and result in protein imbalances (e.g., androgens, prostaglandins, cytokines). These protein imbalances alter cellular functions and signaling, causing, for example, the infiltration of immune system cells, dermal sheath thickening, perifollicular fibrosis, and other physiological factors. Sources of microinflammation in the infundibulum, including microbial flora, toxins, UV radiation, smoking, and pollution, maintain an altered signaling environment.

Figure 4

Manhattan plot depicting the association score as −log10 (p-value) corresponding to 119 significant variants related to androgenetic alopecia. Association scores and variants were retrieved from the GWAS catalog [159].