mTORC1 activity negatively regulates human hair follicle growth and pigmentation

Abstract

Dysregulation of the activity of the mechanistic target of rapamycin complex 1 (mTORC1) is commonly linked to aging, cancer, and genetic disorders such as tuberous sclerosis (TS), a rare neurodevelopmental multisystemic disease characterized by benign tumors, seizures, and intellectual disability. Although patches of white hair on the scalp (poliosis) are considered as early signs of TS, the underlying molecular mechanisms and potential involvement of mTORC1 in hair depigmentation remain unclear. Here, we have used healthy, organ‐cultured human scalp hair follicles (HFs) to interrogate the role of mTORC1 in a prototypic human (mini‐)organ. Gray/white HFs exhibit high mTORC1 activity, while mTORC1 inhibition by rapamycin stimulated HF growth and pigmentation, even in gray/white HFs that still contained some surviving melanocytes. Mechanistically, this occurred via increased intrafollicular production of the melanotropic hormone, α‐MSH. In contrast, knockdown of intrafollicular TSC2, a negative regulator of mTORC1, significantly reduced HF pigmentation. Our findings introduce mTORC1 activity as an important negative regulator of human HF growth and pigmentation and suggest that pharmacological mTORC1 inhibition could become a novel strategy in the management of hair loss and depigmentation disorders.

Topical Minoxidil Rejuvenates Hair Follicles from Men with Androgenetic Alopecia in Vivo

“…Horizontal sections of the xenotransplants before and after transplantation were processed and immunostained as described previously ( 7 ) and are detailed in Table SI . This enabled a comprehensive analysis involving antibodies against lamin B1 ( 13 ), p16INK4A ( 14 ), protein S6 (p-S6) ( 15 ), collagen XVIIA ( 16 ), and biomarkers of mitochondrial activity and/or ageing (MTCO1, PGC1α, SIRT1, and porin/VDAC ), and both human and murine VEGF-A ( 7 ). Finally, we also interrogated oxidative damage responses by immunostaining NRF2 and some of its key downstream targets.…”

Radiation Dermatitis: Radiation-Induced Effects on the Structural and Immunological Barrier Function of the Epidermis

“…In the anagen phase, both mouse and human HFs contain mature melanocytes in the hair matrix, whereas amelanotic melanocytes are also observed in the outer root sheaths and hair bulbs [ 70 ]. Natural hair graying is a gradual, initially reversible process that is characterized by the defective production and transfer of melanosomes, lighter hair pigmentation and reduced mature melanocytes in the HF pigmentary units [ 70 , 71 ]. Radiation-induced human hair graying likely results initially from damage to the intimate crosstalk between the matrix keratinocytes and melanocytes in the hair bulb, which relies on both epithelial and mesenchymal signals for hair pigmentation [ 70 , 72 ].…”

Melatonin Exerts Prominent, Differential Epidermal and Dermal Anti-Aging Properties in Aged Human Eyelid Skin Ex Vivo

“…Cell and tissue aging is associated with increased mTORC1 activity, and the mTORC1 pathway significantly promotes the senescence-associated secretory phenotype of senescent cells [66]. To gauge mTORC1 activity via qIHM, we examined the expression of phosphorylated ribosomal protein S6 (p-S6), a sensitive direct downstream target of mTORC1 signaling, as an aging biomarker [51,67]. This showed a significant reduction in p-S6 protein expression within the epidermis, particularly notable in the stratum spinosum, after three days of culture with a concentration of 200 µM melatonin when compared to the vehicle control group (Figure 1a,b).…”

“…In order to generate proof of principle, we administered melatonin to the culture medium, thus imitating a "systemic" mode of application and circumventing potential confounders arising from topical application, including transcutaneous penetration and intraepidermal melatonin metabolism. Specifically, we asked whether the "systemic" administration of high-dose melatonin (100 µM and 200 µM) [45] significantly changes epidermal S6 phosphorylation (a direct marker of mTORC1 activity [51]), collagen 17A1 (the key stem-cell-niche-associated transmembrane matrix molecule [52][53][54]), Matrix Metalloproteinase 1 (MMP-1, the activity of which is associated with degradation of collagen I and collagen III fibers [55]). We also assessed the protein immunoreactivity of sirtuin-1 ((SIRT-1), which takes part in deacetylation of key substrates-histones or p53-involved in the regulation of cell metabolism and cell cycle [56]), of lamin-B1 (the main component of nuclear lamina stabilizing the nucleus [57,58]), p16 INK4 (tumor suppressor promoting the senescence in cell cycle [59,60]), γH2A.x (phosphorylated histone protein H2A.x, a marker of double-strand breaks in DNA [61]), the mitochondrial markers TFAM, MTCO-1, and VDAC/Porin, since mitochondrial dysfunction is associated with aging [33,47,62,63], and the recently identified key driver of human skin rejuvenation, VEGF-A [3,17].…”