Intrinsic ROS Drive Hair Follicle Cycle Progression by Modulating DNA Damage and Repair and Subsequently Hair
Mingsheng Liu1, Xiaomei Liu1, Yuan Wang1
1Department of Toxicology, School of Public Health, Jilin University, Changchun, China.
Abstract:
Hair follicles (HFs) maintain homeostasis through the hair cycles; therefore, disrupting the hair cycle may lead to hair loss. Our previous study showed that apoptosis-inducing factor (AIF) nuclear translocation and poly [ADP-ribose] polymerase 1 (PARP1) upregulation induced apoptosis in mouse hair follicles during the hair cycle transition from anagen to catagen. However, the mechanism underlying this phenomenon remains unclear. In this study, we found that intrinsic ROS levels increased during the hair follicle cycle transition from anagen to catagen, followed by abrupt DNA breaks and activation of homologous recombinant and nonhomologous end joining DNA repair, along with the enhancement of apoptosis. Mice in different stages of the hair cycle were sacrificed, and the dorsal skins were collected. The results of western blot and histological staining indicated that AIF-PARP1 plays a key role in HF apoptosis, but their role in the regulation of the HF cycle is not clear. Mice were treated with inhibitors from anagen to catagen: treatment with BMN 673, a PARP1 inhibitor, increased DNA breaks and activated the cytochrome c/caspase-3-mediated apoptotic pathway, accelerating HF regression. Ac-DEVD-CHO (Ac), a caspase-3 inhibitor, attenuated HF degeneration by upregulating PARP1 expression, suggesting a seesaw relationship between cytochrome c-caspase-3- and AIF-PARP1-mediated apoptosis, wherein PARP1 may be the fulcrum. In addition, macrophages were involved in regulating the hair cycle, and the rate of M1 macrophages around HFs increased during catagen, while more M2 macrophages were found during anagen and telogen. Our results indicate that intrinsic ROS drive HF cycle progression through DNA damage and repair, followed by apoptosis. Intrinsic ROS drive hair follicle cycle progression by modulating DNA damage and repair, and consecutively, hair follicle apoptosis and macrophage polarization work together to promote the hair follicle cycle.
Insights
Reactive oxygen species (ROS) drive hair follicle cycling by causing DNA damage and repair, leading to apoptosis. Macrophage polarization also plays a role in this hair loss mechanism.
Area of Science:
- Dermatology and Cell Biology
- Investigating the molecular mechanisms of hair follicle cycling and hair loss.
Background:
- Hair follicle (HF) homeostasis is regulated by hair cycles; disruption can cause hair loss.
- Previous studies identified apoptosis-inducing factor (AIF) and poly (ADP-ribose) polymerase 1 (PARP1) in HF apoptosis during the anagen to catagen transition.
- The precise mechanism linking these factors to HF cycle regulation remained unclear.
Purpose of the Study:
- To elucidate the mechanism by which intrinsic reactive oxygen species (ROS) regulate the hair follicle cycle.
- To investigate the roles of DNA damage, repair pathways, apoptosis, and macrophage polarization in HF cycle progression.
Main Methods:
- Analysis of mouse dorsal skin samples at different hair cycle stages.
- Western blot and histological staining to assess protein expression and cellular changes.
- Pharmacological inhibition of PARP1 and caspase-3 to evaluate their effects on HF apoptosis and cycle progression.
Main Results:
- Increased intrinsic ROS levels during the anagen to catagen transition correlated with DNA breaks and enhanced apoptosis.
- PARP1 inhibition accelerated HF regression, while caspase-3 inhibition upregulated PARP1, suggesting a seesaw relationship in apoptosis.
- Macrophage polarization shifted, with increased M1 during catagen and M2 during anagen/telogen.
Conclusions:
- Intrinsic ROS drive HF cycle progression via DNA damage and repair, culminating in apoptosis.
- AIF-PARP1 and cytochrome c-caspase-3 pathways mediate apoptosis in a balanced manner, with PARP1 as a potential fulcrum.
- Macrophage polarization and ROS-induced apoptosis collectively promote hair follicle cycling.
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