mTORC1 activity negatively regulates human hair follicle growth and pigmentation

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. Synopsis Gray/white HFs exhibit high mTORC1 activity, while mTORC1 inhibition by rapamycin stimulates both HF pigmentation and hair growth by prolonging anagen, even in depigmented HFs that still contain some surviving melanocytes. The pigmentary effect occurs via increased intrafollicular production of the melanotropic hormone, α‐MSH. Rapamycin stimulates human scalp hair follicle growth and pigmentation ex vivo via increased α‐MSH production. Knockdown of intrafollicular tuberous sclerosis complex 2 (TSC2), a negative regulator of mTORC1, reduced human scalp hair follicle pigmentation. Rapamycin can restimulate pigmentation in gray/white HFs that still contain surviving melanocytes. Graphical Abstract Gray/white hair follicles exhibit high mTORC1 activity. mTORC1 inhibition by rapamycin stimulates hair follicle growth and pigmentation via increased intrafollicular production of the melanotropic hormone, α‐MSH.