Taisuke Ito

A Hot New Twist to Hair Biology: Involvement of Vanilloid Receptor-1 (VR1/TRPV1) Signaling in Human Hair Growth Control

The vanilloid receptor-1 (VR1, or transient receptor potential vanilloid-1 receptor, TRPV1) is activated by capsaicin, the key ingredient of hot peppers. TRPV1 was originally described on sensory neurons as a central integrator of various nociceptive stimuli. However, several human skin cell populations are also now recognized to express TRPV1, but with unknown function. Exploiting the human hair follicle (HF) as a prototypic epithelial-mesenchymal interaction system, we have characterized the HF expression of TRPV1 in situ and have examined TRPV1 signaling in organ-cultured human scalp HF and outer root sheath (ORS) keratinocytes in vitro. TRPV1 immunoreactivity was confined to distinct epithelial compartments of the human HF, mainly to the ORS and hair matrix. In organ culture, TRPV1 activation by capsaicin resulted in a dose-dependent and TRPV1-specific inhibition of hair shaft elongation, suppression of proliferation, induction of apoptosis, premature HF regression (catagen), and up-regulation of intrafollicular transforming growth factor-beta(2). Cultured human ORS keratinocytes also expressed functional TRPV1, whose stimulation inhibited proliferation, induced apoptosis, elevated intracellular calcium concentration, up-regulated known endogenous hair growth inhibitors (interleukin-1beta, transforming growth factor-beta(2)), and down-regulated known hair growth promoters (hepatocyte growth factor, insulin-like growth factor-I, stem cell factor). These findings strongly support TRPV1 as a significant novel player in human hair growth control, underscore the physiological importance of TRPV1 in human skin beyond nociception, and identify TRPV1 as a promising, novel target for pharmacological manipulations of epithelial growth disorders.

Collapse and Restoration of MHC Class-I-Dependent Immune Privilege : Exploiting the Human Hair Follicle as a Model

The collapse of major histocompatibility complex (MHC) class-I-dependent immune privilege can lead to autoimmune disease or fetal rejection. Pragmatic and instructive models are needed to clarify the as yet obscure controls of MHC class I down-regulation in situ, to dissect the principles of immune privilege generation, maintenance, and collapse as well as to develop more effective strategies for immune privilege restoration. Here, we propose that human scalp hair follicles, which are abundantly available and easily studied, are ideally suited for this purpose: interferon-gamma induces ectopic MHC class I expression in the constitutively MHC class-I-negative hair matrix epithelium of organ-cultured anagen hair bulbs, likely via interferon regulatory factor-1, along with up-regulation of the MHC class I pathway molecules beta(2)microglobulin and transporter associated with antigen processing (TAP-2). In the first report to identify natural immunomodulators capable of down-regulating MHC class I expression in situ in a normal, neuroectoderm-derived human tissue, we show that ectopic MHC class I expression in human anagen hair bulbs can be normalized by treatment with alpha-MSH, IGF-1, or TGF-beta1, all of which are locally generated, as well as by FK506. These agents are promising candidates for immune privilege restoration and for suppressing MHC class I expression where this is clinically desired (eg, in alopecia areata, multiple sclerosis, autoimmune uveitis, mumps orchitis, and fetal or allograft rejection).

Interferon-γ is a potent inducer of catagen-like changes in cultured human anagen hair follicles

Background  Interferon (IFN)‐γ appears to be an important hair cycle modulator in mice. It is unclear whether it has similar hair growth modulatory functions in human hair follicles.

The human hair follicle has established a fully functional peripheral equivalent of the hypothamalic‐pituitary‐adrenal‐axis (HPA)

After the initial discovery that, in vivo, mammalian skin both transcribes and translates the proopiomelanocortin (POMC) gene, and processes its product into melanocortins (Slominski et al., Experientia 1992), it has become increasingly appreciated that the hair follicle – including the human one – is a prime source and target not only of POMC‐derived “pituitary” hormones, e.g. alpha‐MSH, ACTH and ß‐endorphin, but also expresses the most proximal control element of the hypothalamic‐pituitary‐adrenal (HPA) axis, corticotropin‐releasing hormone (CRH) and its receptor (e.g. Roloff et al. FASEB J 1998, Ito et al. J Invest Dermatol 2004). However, while all proximal elements of the HPA are expressed in both murine and human hair follicles (CRH, CHR‐R, POMC, ACTH and ACTH‐R), it has neither been shown that these are functionally linked (i.e., is CRH actually capable of modulating intrafollicular POMC gene expression and ACTH production?), nor has it been known whether the most distal HPA component – cortisol synthesis – is also present in the hair follicle. Therefore, we have investigated whether the stimulation of microdissected, organ‐cultured human hair follicles with CRH or ACTH elicits responses inside this peripheral miniorgan that imitate a functional HPA – in the absence of any systemic or neural connections and under serum‐free culture conditions. Here, we show that CRH stimulation of organ‐cultured human scalp hair follicles in the anagen VI stage of the hair cycle indeed results in significant upregulation of POMC transcription, and of alpha‐MSH, ACTH, MC1, MC2 and glucocorticoid receptor (GR) immunoreactivity in situ (immunofluorescence). ACTH stimulation, in turn, significantly up‐regulates the – already constitutively present!– cortisol‐immunoreactivity as well as cortisol secretion into the culture medium. This represents the first available evidence that normal human skin (more precisely: the hair follicle) can actually synthesize the “adrenal” steroid hormone cortisol in situ, and that this acticity is regulated by the same “hypothalamic” and “pituitary” hormones that operate as key controls of adrenal cortisol synthesis. Moreover, we show that cortisol stimulation exerts classical feedback responses inside the human anagen hair follicle recognized for the central HPA: cortisol up‐regulates GR, while it down‐regulates CRH expression. Given that the HPA operates as the major system for coordinating stress‐responses of the mammalian organism and for integrating them into changing metabolic demands and neuro‐endocrine‐immune signaling circuits, it has fascinating implications (e.g. for general skin physiology and dermatological therapy), and raises most intriguing questions, that human hair follicles are utilizing a fully functional peripheral equivalent of the central HPA.