FGF18 signaling in the hair cycle resting phase determines radioresistance of hair follicles by arresting hair cycling

Abstract

PurposeTelogen (resting phase) hair follicles (HFs) are more radioresistant than their anagen (growth phase) counterparts. Fibroblast growth factor (FGF) 18 is strongly expressed in telogen HFs to maintain the telogen phase, whereas several other FGFs exert radioprotective effects; however, the role of FGF18 in the radioresistance of HFs remains unknown. This study focused on clarifying the role of FGF18 in the radioresistance of telogen HFs and its potential as a radioprotector.Methods and materialsBALB/c mice with telogen or plucking-induced anagen HFs were exposed to total body irradiation with γ-rays at 4 to 12 Gy after intraperitoneal treatment with FGF18 or an FGF receptor inhibitor. A time course analysis was performed histologically and hair growth was observed 14 or 15 days after depilation. Skin specimens were analyzed by DNA microarrays and Western blotting.ResultsTelogen irradiation at 6 Gy resulted in transient cell growth arrest, leading to successful hair growth, whereas anagen irradiation failed to promote hair growth. Telogen irradiation did not induce apoptosis in HFs or reduce HF stem cells, whereas anagen irradiation induced apoptosis and reduced stem cell numbers. The Inhibition of FGF receptor signaling during the telogen phase promoted HF cell proliferation; however, hair failed to grow after irradiation. In contrast, recombinant FGF18 induced transient cell growth arrest after anagen irradiation with enhanced DNA repair, leading to the inhibition of apoptosis, maintenance of HF stem cells, and successful hair growth. Moreover, FGF18 reduced the expression levels of genes promoting G2/M transition as well as the protein expression levels of cyclin B1 and cdc2 in skin, and induced G2/M arrest in the keratinocyte cell line HaCaT.ConclusionsThese results suggest that FGF18 signaling mediates radioresistance in telogen HFs by arresting the cell cycle, and that FGF18 has potential as a radioprotector for radiation-induced alopecia.

IRX5 promotes DNA damage repair and activation of hair follicle stem cells

“…To determine whether upregulation of FGF could mediate the delayed anagen initiation in Irx5 −/− mice, we inhibited the downstream signaling of FGF with the pan-FGFR inhibitor AZD4547 ( Kawano et al., 2016 ). Irx5 −/− mice were treated with 10 μM/g AZD4547 (n = 11) or 1% DMSO saline (n = 9) every two days from P20 to P46.…”

Carbon ions trigger DNA damage response to overcome radioresistance by regulating β‐catenin signaling in quiescent HeLa cells

“…IR activates DNA damage checkpoints to delay cell cycle progression, which provides cells with time to repair the induced damage (Ferguson et al, 2005; Kawano et al, 2016). Different radiation types may have different regulatory mechanisms during the cell cycle.…”

Assessment and Treatment Outcomes of Persistent Radiation-Induced Alopecia in Patients With Cancer

“…7,8,21,[23][24][25][26][27][28] Hair follicle radiosensitivity is also dependent on hair cycle stage: anagen matrix cells are more radiosensitive than telogen matrix cells owing to relative differences in proliferation rates. 8,29 While the dose threshold for transient epilation is low (0.75-2 Gy) [30][31][32] and the singlefraction lethal dose for a hair follicle was historically considered to be 7 to 16 Gy, 7,33,34 the risk factors and dose thresholds for pRIA in patients with cancer receiving modern fractionated CRT are less clear.…”

“…Although mechanisms of pRIA are not well understood, substantive genotoxic insults from radiotherapy or cytotoxic chemotherapy can damage epithelial hair follicle stem cells in the bulge region in addition to the rapidly dividing hair matrix cells in the hair follicle bulb, preferentially causing an anagen effluvium that is histologically consistent with nonspecific scarring alopecia . Hair follicle radiosensitivity is also dependent on hair cycle stage: anagen matrix cells are more radiosensitive than telogen matrix cells owing to relative differences in proliferation rates . While the dose threshold for transient epilation is low (0.75-2 Gy) and the single-fraction lethal dose for a hair follicle was historically considered to be 7 to 16 Gy, the risk factors and dose thresholds for pRIA in patients with cancer receiving modern fractionated CRT are less clear.…”