Multiple potential roles of thymosin β4 in the growth and development of hair follicles

Abstract

The hair follicle (HF) is an important mini-organ of the skin, composed of many types of cells. Dermal papilla cells are important signalling components that guide the proliferation, upward migration and differentiation of HF stem cell progenitor cells to form other types of HF cells. Thymosin β4 (Tβ4), a major actin-sequestering protein, is involved in various cellular responses and has recently been shown to play key roles in HF growth and development. Endogenous Tβ4 can activate the mouse HF cycle transition and affect HF growth and development by promoting the migration and differentiation of HF stem cells and their progeny. In addition, exogenous Tβ4 increases the rate of hair growth in mice and promotes cashmere production by increasing the number of secondary HFs (hair follicles) in cashmere goats. However, the molecular mechanisms through which Tβ4 promotes HF growth and development have rarely been reported. Herein, we review the functions and mechanisms of Tβ4 in HF growth and development and describe the endogenous and exogenous actions of Tβ4 in HFs to provide insights into the roles of Tβ4 in HF growth and development.

Keywords: development; growth; hair follicle; thymosin β4.

FIGURE 1

Schematic representation and terminology of the structure of the hair follicle. The hair shaft (HS) consists of the medulla (M), hair cortex (Cx) and hair cuticle (Ce). The inner root sheath (IRS) consists of the cuticle of the inner root sheath (Ci), Huxley's layer (Hx) and Henle's layer (He). The companion layer (Cp) is occasionally referred to as a member of the outer root sheath (ORS), which includes the hair matrix (Mx) and dermal papilla (DP)

FIGURE 2

Schematic representation of β‐thymosins. (A) Comparison of β‐thymosins expressed in human beings. Proteolytic cleavage (orange arrow) leads to the generation of an acetylated tetrapeptide. Methionine residues in Tβ4 and Tβ10 can be oxidized to methionine sulfoxide residues (orange letters). Glutamine residues (green labelled with green arrows) are glutaminyl donors in transglutaminase reactions. (B) The secondary structure of Tβ4. Thymosins in aqueous solution are unstructured and flexible. The actin‐binding motif (‐LKKTET‐) is responsible for the initial interaction with G‐actin, which induces the formation of two helices (shown simplified). Residues 1‐5 contact subdomain 3 of G‐actin. The N‐terminal helix of Tβ4 contacts subdomain 1 of G‐actin. The residues between the N‐terminal and C‐terminal helices expand on subdomain 2. The C‐terminal helix contacts subdomain 2 and may close the cleft between subdomains 2 and 4. Tβ4 binds to G‐actin in an extended conformation and thus blocks salt‐induced actin polymerization by steric hindrance. (C) Possible 3D structure of Tβ4. The structure for Tβ4 was visualized using the PyMOL program

FIGURE 3

Tβ4 increases hair growth by the activation of hair follicle stem cells. (A) Hair follicle transition to early anagen phase was associated with an increased number of Tβ4‐expressing cells in the bulge region. Moreover, some Tβ4‐positive–stained cells were detected in the lower part of the follicle, between the bulge and bulb area. (B) At late anagen phase, a significant number of the cells located in the lower follicle expressed Tβ4. (C) At catagen phase, the number of Tβ4‐expressing cells should theoretically decrease. Philp et al showed that during this process, Tβ4‐positive cells expressed patterns similar to those of hair follicle stem cells (D) Low levels of Tβ4 were observed in follicles at the telogen phase. In these follicles, Tβ4 expression was confined to a small number of cells residing in the bulge region. (E) The roots of the hair fall off and new hair forms at the base of the hair follicle ³⁴

FIGURE 4

Timeline of research on the effects of exogenous Tβ4 in hair follicle growth and development

FIGURE 5

Potential signalling pathways of Tβ4 in hair follicle growth and development. There are three main signalling pathways: Wnt/β‐catenin, phosphatidylinositol 3‐kinase (PI3K)/AKT and matrix metalloproteinase (MMP)‐2. VEGF: vascular endothelial growth factor; VEGFR: VEGF receptor; eNOS: endothelial nitric oxide synthase; NO: nitric oxide; ER: endoplasmic reticulum; FZD: frizzled; DVL: dishevelled; APC: adenomatous polyposis coli