Autophagy induces hair follicle stem cell activation and hair follicle regeneration by regulating glycolysis

Abstract

Abstract Background Hair follicle stem cells (HFSCs) are usually in a resting state and are activated during the transition from telogen to anagen phases to ensure that the hair follicle enters a new cycle. Macroautophagy/autophagy regulates stem cell metabolic behavior in tissues, and changes in HFSC metabolism directly affect HFSC activation and maintenance. However, the role of autophagy in the regulation of HFSC metabolism and function remains unclear. Methods Back hair of mice at different hair follicle cycle stages was collected, and immunofluorescence staining was used to detect changes in HFSC autophagy levels in the hair follicle cycle. Mouse and human hair follicles were treated with rapamycin (Rapa, an autophagy activator) and 3-methyladenine (3-MA, an autophagy inhibitor). The effects of autophagy on the hair follicle cycle and HFSC were investigated by imaging, cell proliferation staining, and HFSC-specific marker staining. The influence and mechanism of autophagy on HFSC metabolism were explored by RNA sequencing, real-time polymerase chain reaction (PCR), immunohistochemical staining, and lactate and glucose detection. Finally, the influence of autophagy-induced glycolysis on HFSC and the hair follicle cycle was verified by proliferation, stem cell characteristics, and in vivo functional experiments. Results The HFSC autophagy level in hair follicles was highest during the transition from the telogen to the anagen phase. The inhibition of autophagy with 3-MA led to early entry into the catagen phase and a prolonged telogen phase, whereas Rapa promoted autophagy and hair growth. Autophagy activated HFSC by increasing the activity of HFSC lactate dehydrogenase (Ldha) and lactate production and transforming HFSC metabolism into glycolysis. The inhibition of Ldha expression counteracted the effects of autophagy. Conclusions These results demonstrated that autophagy activated HFSC by promoting the transition from HFSC metabolism to glycolysis, ultimately initiating the hair follicle cycle and promoting hair growth.