Background: Hair follicle stem cells (HFSCs) typically remain quiescent and are activated only during the transition from telogen to anagen to ensure that the hair follicle enters a new cycle. The metabolic behavior of stem cells in tissues is regulated by macroautophagy/autophagy, and changes in HFSC metabolism directly affect their activation and maintenance. However, the role of autophagy in the regulation of HFSC metabolism and function remains unclear. Methods: Back skin samples were obtained from mice at different hair follicle cycle stages, and immunofluorescence staining was used to monitor autophagy in HFSCs. Mouse and human hair follicles were treated with rapamycin (Rapa, an autophagy activator) or 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 using RNA sequencing, real-time polymerase chain reaction, immunohistochemical staining, and detection of lactate and glucose concentrations. Finally, the influence of autophagy-induced glycolysis on HFSC and the hair follicle cycle was verified by stem cell characteristics and in vivo functional experiments. Results: Autophagy in HFSC was highest during the transition from telogen to anagen. Inhibiting autophagy with 3-MA led to early entry into catagen and prolonged telogen, whereas Rapa promoted autophagy and hair growth. Autophagy activated HFSC by increasing the expression and activity of HFSC lactate dehydrogenase (Ldha), thereby transforming HFSC metabolism into glycolysis. Inhibition of Ldha expression counteracted the effects of autophagy. Conclusions: Autophagy activated HFSC by promoting the transition from HFSC metabolism to glycolysis, ultimately initiating the hair follicle cycle and promoting hair growth. Graphical

Hair loss is a debilitating condition associated with the depletion of dermal papilla cells (DPCs), which can be replenished by dermal sheath cells (DSCs). Hence, strategies aimed at increasing the populations of DPCs and DSCs hold promise for the treatment of hair loss. In this study, we demonstrated in mice that introduced exogenous DPCs and DSCs (hair follicle mesenchymal stem cells) could effectively migrate and integrate into the dermal papilla and dermal sheath niches, leading to enhanced hair growth and prolonged anagen phases. However, the homing rates of DPCs and DSCs were influenced by various factors, including recipient mouse depilation, cell passage number, cell dose, and immune rejection. Through in vitro and in vivo experiments, we also discovered that the CXCL13/CXCR5 pathway mediated the homing of DPCs and DSCs into hair follicle niches. This study underscores the potential of cell-based therapies for hair loss by targeted delivery of DPCs and DSCs to their respective niches and sheds light on the intriguing concept that isolated mesenchymal stem cells can home back to their original niche microenvironment.

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.