Highlights
- •PGE2 pretreatment attenuates radiotherapy-induced hair loss.
- •Locally administered PGE2 reduces the radiosensitivity of HF TACs by transiently arresting them in G1 phase.
- •TACs are protected from radiation-induced apoptosis when radiation is delivered in the time window of higher radioresistance.
- •Preservation of more TACs converts a dystrophic catagen to a dystrophic anagen response, and thus reduces hair loss.
Abstract
Background
Growing hair follicles (HFs) harbor actively dividing transit amplifying cells (TACs),
rendering them highly sensitive to radiotherapy (RT). Clinically, there is still a
lack of treatment options for radiotherapy-induced alopecia (RIA).
Objective
Our present study aimed to investigated the effect and mechanism of local prostaglandin
E2 (PGE2) treatment in RIA prevention.
Methods
We compared the response of growing HFs to radiation with and without local PGE2 pretreatment
in a mouse model in vivo. The effect of PGE2 on the cell cycle was determined in cultured
HF cells from fluorescent ubiquitination-based cell cycle indicator mice. We also
compared the protective effects of PGE2 and a cyclin-dependent kinases 4/6 (CDK4/6)
inhibitor against RIA.
Results
The local cutaneous PGE2 injection reduced RIA by enhancing HF self-repair. Mechanistically,
PGE2 did not activate HF stem cells, but it preserved more TACs for regenerative attempts.
Pretreatment of PGE2 lessened radiosensitivity of TACs by transiently arresting them
in the G1 phase, thereby reducing TAC apoptosis and mitigating HF dystrophy. The preservation
of more TACs accelerated HF self-repair and bypassed RT-induced premature termination
of anagen. Promoting G1 arrest by systemic administration of palbociclib isethionate
(PD0332991), a CDK4/6 inhibitor, offered a similar protective effect against RT.
Conclusions
Locally administered PGE2 protects HF TACs from RT by transiently inducing G1 arrest,
and the regeneration of HF structures lost from RT is accelerated to resume anagen
growth, thus bypassing the long downtime of hair loss. PGE2 has the potential to be
repurposed as a local preventive treatment for RIA.
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Article info
Publication history
Published online: February 20, 2023
Accepted:
February 16,
2023
Received in revised form:
January 15,
2023
Received:
October 11,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
