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Hair follicle is a skin appendage that shows cyclic activity in postnatal life with periods of active growth and hair formation (anagen), rapid apoptosis-driven involution (catagen), and relative resting (telogen).^23–25 Hair follicle transition between distinct hair cycle stages is governed by epithelial-mesenchymal interactions between the follicular keratinocytes and dermal papilla fibroblasts.^24–26 Growth factors forming a molecular network of signals that the epithelium and the mesenchyme send to each other during the hair cycle belong to the Wnt, transforming growth factor-/bone morphogenetic protein (BMP), Hedgehog, fibroblast growth factor, Notch, epidermal growth factor, tumor necrosis factor, and neurotrophin families.^24–26

Accumulating evidence of the data suggests that neurohormones, neurotransmitters, and cytokines released during the stress response may also significantly influence the hair cycle.^13,27 Actively growing hair follicles in mice and humans show expression of CRH-R1 and melanocortin- 1 receptor (MC-1R) in the follicular epithelium and mesenchyme.^11,13,14 Administration of ACTH into murine telogen skin causes mast cell deregulation and activation of hair growth in resting hair follicles.²⁸ However, ACTH treatment also induces premature hair follicle anagen-catagen transition.²⁹ Similarly to the stress-induced thymic involution, glucocorticoids stimulate apoptosis in the follicular epithelium leading to premature hair follicle involution.³⁰ Thus, the effects of neurohormones on hair follicle growth seem to be more complex than previously appreciated and strongly depend of hair cycle stage.

The hair follicle is richly innervated by sensory and autonomic nerve fibers. In murine dorsal skin, nerve fibers that innervate hair follicles form two networks: around the distal outer root sheath in the subepidermal dermis (follicular network A) and around the outer root sheath between the sebaceous gland and the insertion point of the arrector pili muscle (follicular network B).^31–33 The follicular network A consists of unmyelinated C-fibers expressing such neuropeptides as substance P, calcitonin gene-related peptide, peptide-histidine-methionin (PHM), and the enzymes choline acetyltransferase and tyrosine hydroxylase.^32,33 Follicular network B consists of a collar of longitudinal and circular nerve fibers arranged in the manner of a palisade around the outer root sheath of the hair follicle. These nerve fibers function as slowly adapting mechanoreceptors and show expression of calcitonin gene-related peptide and choline acetyltransferase.^5,32,33 Together they fill the space between the sebaceous gland and the hair follicle epithelium adjacent to the bulge region and distal to the arrector pili muscle. In human hair follicles, substance P-positive nerves are also found in the dermal papilla.³⁴

The hair follicle bulge region contains a population of putative hair follicle stem cells.^35–37 A close localization of sensory and autonomic nerve fibers and hair follicle bulge raises a possibility that neuropeptides and neurotransmitters may influence stem cells or their progeny and modulate hair cycle.²⁷ Indeed, bulge keratinocytes show expression of 2-adrenoreceptors and neurokinin-1 receptor³² (Botchkarev et al, unpublished observations). Treatment of telogen mice by substance P or by noradrenaline- depleting agents lead to stimulation of hair growth, whereas substance P administration into anagen skin results in premature catagen development.^29,38 Recent data suggest that denervation of murine skin leads to down-regulation of expression of hair keratin genes.³⁹ Taken together, these data suggest that neurohormones, neuropeptides, and neurotransmitters may significantly influence cyclic activity of the hair follicle further supporting the hypothesis that hair follicles represent an important target for stressors.

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