sirolimus and Alopecia

Hair plays important roles, ranging from the conservation of body heat to the preservation of psychological well-being. Hair loss or alopecia affects millions worldwide, but methods that can be used to regrow hair are lacking. We report that quiescent (telogen) hair follicles can be stimulated to initiate anagen and hair growth by small molecules that activate autophagy, including the metabolites α-ketoglutarate (α-KG) and α-ketobutyrate (α-KB), and the prescription drugs rapamycin and metformin, which impinge on mTOR and AMPK signaling. Stimulation of hair growth by these agents is blocked by specific autophagy inhibitors, suggesting a mechanistic link between autophagy and hair regeneration. Consistently, increased autophagy is detected upon anagen entry during the natural hair follicle cycle, and oral α-KB prevents hair loss in aged mice. Our finding that anagen can be pharmacologically activated in telogen skin when natural anagen-inducing signal(s) are absent has implications for the treatment of hair loss patients.

Topics: Aging; Allyl Compounds; Alopecia; AMP-Activated Protein Kinases; Animals; Autophagy; Butyrates; Cell Division; Female; Hair; Hair Follicle; Ketoglutaric Acids; Male; Metformin; Mice; Mice, Inbred C57BL; Oligomycins; Quinazolines; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases

Transit amplifying cells (TACs) are highly proliferative in nature and tend to be sensitive to ionizing radiation. Due to the abundance of TACs that support the elongation of hair shafts, growing hair follicles are highly sensitive to radiation injury. How hair follicles repair themselves after radiation injury is unclear. In this study, we observed that in 4 Gy irradiated mice, hair follicle dystrophy was induced with apoptosis-driven loss of hair matrix cells, which are the TACs that fuel hair growth. The dystrophy was repaired within 96 h without significant hair loss, indicating that a regenerative attempt successfully restored the TAC population to resume anagen growth. Soon after irradiation, mTORC1 signaling was activated in the TAC compartment and its activation was maintained until the regeneration process was completed. Inhibition of mTORC1 by rapamycin treatment increased radiation-induced cell apoptosis, reduced cell proliferation and delayed restoration of Wnt signaling in the hair matrix after radiation injury, leading to prolonged dystrophy and hair loss. These results demonstrate that mTORC1 signaling is activated after irradiation and is required for timely regeneration of the TAC pool of hair follicles, so that hair growth can resume after radiation injury.

Topics: Alopecia; Animals; Apoptosis; Atrophy; Female; Hair; Hair Follicle; Mechanistic Target of Rapamycin Complex 1; Mice; Radiation Injuries, Experimental; Regeneration; Signal Transduction; Sirolimus; Wnt Signaling Pathway

Topics: Alopecia; Animals; Antibodies, Monoclonal; Combined Modality Therapy; Dose-Response Relationship, Drug; Drug Administration Schedule; Graft Rejection; Graft Survival; Hair; Haplorhini; Injections, Intravenous; Intercellular Adhesion Molecule-1; Models, Animal; Random Allocation; Risk Assessment; Sensitivity and Specificity; Sirolimus; Skin Transplantation; Transplantation, Homologous

Topics: Acne Vulgaris; Alopecia; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Azasteroids; Cantharidin; Cetuximab; Dutasteride; Female; Humans; Male; Molluscum Contagiosum; Sirolimus