Biomolecules & Therapeutics  https://doi.org/10.4062/biomolther.2021.022
ER71/ETV2 Promotes Hair Regeneration from Chemotherapeutic Drug-Induced Hair Loss by Enhancing Angiogenesis
Tae-Jin Lee1,2,†, Hee-Kyoung Kang3,4,†,*, Jeffrey C. Berry5, Hong-Gu Joo6, Changwon Park7, Mark J. Miller5 and Kyunghee Choi1,*
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
2Department of Bio-Health Convergence, Kangwon National University, Chuncheon 24341, Republic of Korea
3Department of Pharmacology, School of Medicine, Jeju National University, Jeju 63243, Republic of Korea
4Jeju Research Center for Natural Medicine, Jeju National University, Jeju 63243, Republic of Korea
5Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA
6College of Veterinary Medicine, Jeju National University, Jeju 63243, Republic of Korea
7Department of Molecular and Cellular Physiology, Louisiana State University Health Science Center, Shreveport, LA 71103, USA
*E-mail: pharmkhk@jejunu.ac.kr (Kang HK), kchoi@wustl.edu (Choi K)
Tel: +82-64-754-3846 (Kang HK), +1-314-362-8716 (Choi K)
Fax: +82-64-702-2687 (Kang HK), +1-314-362-8888 (Choi K)
†The first two authors contributed equally to this work.
Received: January 27, 2021; Revised: February 19, 2021; Accepted: March 15, 2021; Published online: April 5, 2021.
© The Korean Society of Applied Pharmacology. All rights reserved.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Chemotherapy-induced alopecia and hair loss can be stressful in patients with cancer. The hair grows back, but sometimes the hair tends to stay thin. Therefore, understanding mechanisms regulating hair regeneration may improve the management of chemotherapy-induced alopecia. Previous studies have revealed that chemotherapeutic agents induce a hair follicle vascular injury. As hair growth is associated with micro-vessel regeneration, we postulated that the stimulation of angiogenesis might enhance hair regeneration. In particular, mice treated with 5-fluorouracil (5-FU) showed delayed anagen initiation and reduced capillary density when compared with untreated controls, suggesting that the retardation of anagen initiation by 5-FU treatment may be attributed to the loss of perifollicular micro-vessels. We investigated whether the ETS transcription factor ETV2 (aka ER71), critical for vascular development and regeneration, can promote angiogenesis and hair regrowth in a 5-FU-induced alopecia mouse model. Tie2-Cre; Etv2 conditional knockout (CKO) mice, which lack Etv2 in endothelial cells, presented similar hair regrowth rates as the control mice after depilation. Following 5-FU treatment, Tie2-Cre; Etv2 CKO mice revealed a significant reduction in capillary density, anagen induction, and hair restoration when compared with controls. Mice receiving lentiviral Etv2 injection after 5-FU treatment showed significantly improved anagen induction and hair regrowth. Two-photon laser scanning microscopy revealed that enforced Etv2 expression restored normal vessel morphology after 5-FU mediated vessel injury. Our data suggest that vessel regeneration strategies may improve hair regrowth after chemotherapeutic treatment.
Keywords: Angiogenesis, Chemotherapy-induced alopecia, ETS transcription factor, ETV2/ER71, Hair regeneration, 5-FU

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