FGF18 Signaling for Hair Cycle Resting Phase Determines Radioresistance of Hair Follicles by the Arrest of Hair Cycling

Telogen (resting phase) hair follicles are more radioresistant than anagen (growth phase) ones. Irradiation of BALB/c mice in the anagen phase with γ-rays at 6 Gy induced hair follicle dystrophy, whereas irradiation in the telogen phase induced the arrest of hair follicle elongation without any dystrophy after post-irradiation depilation. In contrast, FGF18 was highly expressed in the telogen hair follicles to maintain the telogen phase and also the quiescence of hair follicle stem cells. Therefore, the inhibition of FGF receptor signaling at telogen induced the dystrophy after post-irradiation depilation. In addition, the administration of recombinant FGF18 suppressed cell proliferation in the hair follicles and enhanced the repair of radiation-induced DNA damage, so FGF18 protected the anagen hair follicles against radiation damage to enhance hair regeneration. Moreover, FGF18 reduced the expression of cyclin B1 and cdc2 in the skin and FGF18 signaling induced G2/M arrest in the keratinocyte cell line HaCaT, although no obvious change of the expression of DNA repair genes was detected by DNA microarray analysis. These findings suggest that FGF18 signaling for the hair cycle resting phase causes radioresistance in telogen hair follicles by arresting the proliferation of hair follicle cells. Portions of dorsal skin of 7-week-old male BALB/c mice were depilated to induce anagen phase of hair follicles. One hundred micrograms of FGF18 diluted in saline containing 5 μg/μl heparin was administered intraperitoneally to mice 6 days after depilation, and then mice were subjected to total body irradiation with γ-rays at 6 Gy 24 h after FGF administration. The skin was removed from treated mice 4 h after irradiation and total RNAs were isolated from the skin. The mRNA expression profiles were obtained using Affymetrix GeneChip Mouse Gene 2.0 ST Array (Affymetrix, Santa Clara, CA, USA).