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Hair follicles (HFs) maintain a peripheral, functional equivalent of the hypothalamic-pituitary-adrenal (HPA) axis, whose most proximal element is corticotropin-releasing hormone (CRH). The mast cell (MC)-rich connective-tissue sheath (CTS) of mouse vibrissa HFs harbors MC precursors. Differentiation of these MC precursors into mature MCs can be induced by stem cell factor (SCF). We have investigated whether the MC progenitors of normal human scalp HF CTS respond to stimulation with CRH. Microdissected anagen HFs and full-thickness scalp skin were treated with CRH (10(-7) M). CRH treatment induced the degranulation of CTS MCs, in addition to increasing the number of CTS MCs in full-thickness skin and HF organ cultures in situ. In the latter, cells with characteristic MC features emigrated from the CTS. CRH-receptor protein expression in the CTS was colocalized with Kit expression on some CTS MCs in situ. CRH treatment upregulated SCF mRNA and protein expression within the HF epithelium. In skin organ culture, CRH-induced degranulation of CTS MCs was abolished by anti-SCF antibody. We demonstrate that human skin is an extramedullary reservoir for MC precursors, and we have identified a regulatory loop between CRH and SCF signaling. This highlights a previously unpublished finding about neuroendocrine control of human MC biology.

Pituitary thyroid-stimulating hormone (TSH) regulates thyroid hormone synthesis via receptors (TSH-R) expressed on thyroid epithelial cells. As the hair follicle (HF) is uniquely hormone-sensitive and, hypothyroidism with its associated, increased TSH serum levels clinically can lead to hair loss, we asked whether human HFs are a direct target for TSH. Here, we report that normal human scalp skin and microdissected human HFs express TSH-R mRNA. TSH-R-like immunoreactivity is limited to the mesenchymal skin compartments in situ. TSH may alter HF mesenchymal functions, as it upregulates alpha-smooth muscle actin expression in HF fibroblasts. TSH-R stimulation by its natural ligand in organ culture changes the expression of several genes of human scalp HFs (for example keratin K5), upregulates the transcription of classical TSH target genes and enhances cAMP production. Although the functional role of TSH in human HF biology awaits further dissection, these findings document that intracutaneous TSH-Rs are fully functional in situ and that HFs of female individuals are direct targets for nonclassical, extrathyroidal TSH bioregulation. This suggests that organ-cultured scalp HFs provide an instructive and physiologically relevant human model for exploring nonclassical functions of TSH, in and beyond the skin.