Erythropoietin promotes hair shaft growth in cultured human hair follicles and modulates hair growth in mice Bo Mi Kang a , Seung Hyun Shin a , Mi Hee Kwack a , HyeRim Shin a , Ji Won Oh a , Jinoh Kim a , Chanil Moon b , Cheil Moon c , Jung Chul Kim a , Moon Kyu Kim a, **, Young Kwan Sung a, * a Department of Immunology, School of Medicine, Kyungpook National University, 101 Dong-In-Dong, Jung-Gu, Daegu 700-422, Republic of Korea b Department of Cardiology, Gil Medical Center, Gachon University, 1198 Guwol-dong, Namdong-gu, Incheon 405-760, Republic of Korea c Department of Brain Science, Daegu Gyeongbuk Institute of Science & Technology, 1188 Dalgubeoldaero(St.), Jung-gu, Daegu 700-742, Republic of Korea 1. Introduction The glycoprotein hormone erythropoietin (EPO) has compact globular structure consisting of four alpha-helical bundles with a molecular mass of 30.4 kDa [1–4]. EPO is produced by the kidney in response to hypoxia and is known to be a specific stimulator of erythropoiesis in hematopoietic tissues by stimulating prolifera- tion and differentiation, and inhibition of apoptosis of erythroid progenitor cells [4,5]. In nonhematopoietic tissues including brain and kidneys, EPO is known to prevent apoptotic cell death caused by hypoxia, cytotoxic drugs and mechanical stress [4,6]. EPO binding to EPOR induces phosphorylation of the EPOR and activation of enzymes and transcription factors such as PI3K/ Akt, MAPK, and STAT5 [4]. The mammalian hair follicle contains dermal papilla (DP) and dermal sheath derived from the mesenchyme. It also contains epithelial cells of the outer root sheath (ORS), inner root sheath, matrix and hair shaft, derived from the epithelium [7]. The postnatal hair follicle undergoes a cycle of anagen (growth phase), catagen (regression phase) and telogen (resting phase). The reciprocal interactions between the epithelium and mesenchyme are essential for postnatal hair growth and cycling of hair follicles [8]. The DP is known to play a key role in the regulation of hair growth and is encapsulated by the overlying epithelial cells during anagen, and factors from the DP are believed to cause epithelial cells to proliferate and differentiate to produce the hair shaft [9]. Recent studies have shown that EPO/EPOR signaling exist in hair follicle (HF). LeBaron et al. [10] showed that dermal papilla cells (DPCs) in mouse HF respond to EPO by analyzing STAT5 activation status. More recently, based on following observations, Bodo ´ et al. [11] showed that human scalp hair follicles are an extrarenal site of EPO production and an extrahematopoietic target of EPO. (1) EPO immunoreactivity was mainly found in ORS cells. Journal of Dermatological Science 59 (2010) 86–90 ARTICLE INFO Article history: Received 21 December 2009 Received in revised form 26 April 2010 Accepted 27 April 2010 Keywords: Dermal papilla EPO EPOR Hair follicle Hair cycle ABSTRACT Background: Recent studies have shown that erythropoietin (EPO)/erythropoietin receptor (EPOR) signaling exist in both human and mouse hair follicles (HFs). Objective: To investigate whether dermal papilla cells (DPCs) express functional EPOR and, if so, to investigate effects of EPO on hair shaft growth in cultured human scalp hair follicles and hair growth in mice. Methods: EPOR expression in DPCs and follicular keratinocytes was examined by RT-PCR and immunoblot. Phosphorylation of EPOR signaling pathway mediators by EPO treatment was examined by immunoblot. MTT assay was employed to check cell viability after EPO treatment. Hair shaft growth was measured in the absence or presence of EPO and matrix keratinocyte proliferation was examined by Ki-67 immunostaining in cultured hair follicles. Agarose beads containing EPO were implanted into dorsal skin of C57BL/6 mice to examine effects of EPO on hair growth in vivo. Results: EPOR mRNA and protein are expressed in cultured human DPCs. EPOR signaling pathway mediators such as EPOR and Akt are phosphorylated by EPO in DPCs. EPO significantly promoted the growth of DPCs and elongated hair shafts with increased proliferation of matrix keratinocytes in cultured human hair follicles. In addition, EPO not only promoted anagen induction from telogen but also prolonged anagen phase. Conclusions: EPO may modulate hair growth by stimulating DPCs that express functional EPOR. ß 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. * Corresponding author. Tel.: +82 53 420 4874; fax: +82 53 423 4628. ** Corresponding author. Tel.: +82 53 420 4876; fax: +82 53 423 4628. E-mail addresses: moonkim@knu.ac.kr (M.K. Kim), ysung@knu.ac.kr (Y.K. Sung). Contents lists available at ScienceDirect Journal of Dermatological Science journal homepage: www.elsevier.com/jds 0923-1811/$36.00 ß 2010 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jdermsci.2010.04.015