Platelet factor 4 inhibits human hair follicle growth and promotes androgen receptor expression in human dermal papilla cells

Platelet factor 4 inhibits human hair follicle growth and promotes androgen receptor expression in human dermal papilla cells Ke Sha1 ,2 ,3 ,4 ,5 , Mengting Chen1 ,2 ,3 , Fangfen Liu1 , San Xu1 ,2 , Ben Wang1 , Qinqin Peng1 ,2 , Yiya Zhang1 ,2 , Hongfu Xie1 ,2 ,3 ,4 , Ji Li1 ,2 ,3 ,4 and Zhili Deng1 ,2 ,3 ,4 1 Department of Dermatology, Xiangya Hospital, Central South University, Changsha, China National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China 3 Key Laboratory of Molecular Radiation Oncology Hunan Province, Central South University, Changsha, China 4 Key Laboratory of Organ Injury, Aging and Regenerative Medicine of Hunan Province, Central South University, Changsha, China 5 Xiangya International Academy of Translational Medicine, Central South University, Changsha, China 2 ABSTRACT Submitted 12 February 2020 Accepted 13 August 2020 Published 4 September 2020 Corresponding author Zhili Deng, Academic editor Rajesh Singh Additional Information and Declarations can be found on page 9 DOI 10.7717/peerj.9867 Copyright 2020 Sha et al. Distributed under Creative Commons CC-BY 4.0 OPEN ACCESS Platelet-rich plasma (PRP) has been reported recently as a potential therapeutic approach for alopecia, such as androgenetic alopecia, but the exact mechanisms and effects of specific components of this recipe remain largely unknown. In this study, we identified that platelet factor 4 (PF4), a component of PRP, significantly suppressed human hair follicle growth and restrained the proliferation of human dermal papilla cells (hDPCs). Furthermore, our results showed that PF4 upregulated androgen receptor (AR) in human dermal papilla cells in vitro and via hair follicle organ culture. Among the hair growth-promoting and DP-signature genes investigated, PF4 decreased the expression of Wnt5a, Wnt10b, LEF1, HEY1 and IGF-1, and increased DKK1 expression, but did not affect BMP2 and BMP4 expression. Collectively, Our data demonstrate that PF4 suppresses human hair follicle growth possibly via upregulating androgen receptor signaling and modulating hair growth-associated genes, which provides thought-provoking insights into the application and optimization of PRP in treating hair loss. Subjects Cell Biology, Molecular Biology, Andrology, Dermatology, Translational Medicine Keywords Hair loss, Hair follicle, Platelet-rich plasma, Platelet factor 4, Androgen receptor, Dermal papilla cells INTRODUCTION The hair follicle (HF) is able to repeatedly go through cycles of degeneration (catagen), rest (telogen), and regeneration (anagen) over all adult life. The hair follicle cycle depends on the capability of HF stem cells (HFSCs), residing in the bulge, to temporarily escape from their quiescent state to start the anagen phase. The activities of HFSCs are mainly regulated by the dermal papilla (DP) in the bottom of hair follicles (Deng et al., 2015; Schneider, Schmidt-Ullrich & Paus, 2009). The DPCs function as the signaling center to govern the How to cite this article Sha K, Chen M, Liu F, Xu S, Wang B, Peng Q, Zhang Y, Xie H, Li J, Deng Z. 2020. Platelet factor 4 inhibits human hair follicle growth and promotes androgen receptor expression in human dermal papilla cells. PeerJ 8:e9867 http://doi.org/10.7717/peerj.9867 behaviors of HFSCs and their descendent cells to achieve hair regeneration (Morgan, 2014). Numerous signals from DP, such as Wnt/β-catenin and BMP signals have been shown to be essential for the hair growth (Deng et al., 2015; Plikus, 2012; Tang et al., 2016; Li et al., 2012). Various hair loss disorders are mainly featured by the incapability of rebooting the growth phase of the hair follicle cycle. In androgenetic alopecia (AGA), elevated androgen receptor (AR) in DP cells is one of the causal factors for AGA (Premanand & Reena, 2018). The dysregulation of androgen receptor signaling affects the production of hair growthassociated paracrine signals in the DP cells. Disruption of these signals hampers HFSCs proliferation and differentiation, causing anagen shortening, thus leading to progressive miniaturization of hair follicles, which is a major feature of AGA (Ceruti, Leiros & Balana, 2018; Qi & Garza, 2014; Shin et al., 2013; Kwack et al., 2008). As a consequence, DP cells are considered as the major therapy target for AGA. The existing therapies are mostly designed to restrain further hair loss, and the efficacy of new hair growth with these therapies are not dissatisfactory and obviously ameliorating effect is not always achieved (Stevens & Khetarpal, 2019). PRP is a derivative of whole blood, also known as autologous conditioned plasma (Mussano et al., 2016). PRP was originally applied to the medical field as a promising hemostatic approach suitable for surgical setting and wound healing (Cieslik-Bielecka et al., 2012; Nicoli et al., 2015). Recently, this technique has been explored in the field of dermatology including wound healing, scar revision, skin rejuvenation, fat graft and so on (Emer, 2019). Furthermore, PRP has also been demonstrated as an efficient cure to treat hair disorders, such as androgenetic alopecia, owing to its autologous, least injuries, less adverse effects, and more acceptable cost in comparison to hair implantation (Strazzulla et al., 2018). Evidence indicates that when injected into scalp, platelets in PRP become activated and secrete a series of cytokines andgrowth factors , like insulin like growth factor-1 (IGF-1), platelet-derived growth factor and epidermal growth factor from their alpha granules, which may promote hair growth (Mussano et al., 2016; Emer, 2019; Cervantes et al., 2018). However, the exact mechanisms and roles of specific components of PRP remain largely unresolved. PF4, as an important member of the CXC chemokine family of small proteins, is one of the richest factors secreted to plasma after blood platelets activation. Even then, its level in plasma is only up to the nanogram level per milliliter (Gleissner, Von Hundelshausen & Ley, 2008; Chen et al., 2020; Makarewicz-Wujec et al., 2020). It has been reported to have an antiproliferative effect on fibroblasts and endothelial cells, but there is no report about its role in human hair growth. Here, we demonstrated that PF4, a component of PRP, notably suppressed human hair follicle growth and inhibited the proliferation of human derma papilla cells. Mechanically, we showed that PF4 promoted the expression of AR in human dermal papilla cells in vitro and via hair follicle organ culture. Among the hair growth-promoting and DP-signature genes investigated, PF4 reduced the expression of Wnt5a, Wnt10b, LEF1, HEY1 and IGF-1, and increased the expression of DKK1, but did not alter the expression of BMP2 and BMP4. Taken together, Our findings reveal that PF4 inhibits human hair follicle growth possibly by enhancing androgen receptor signaling Sha et al. (2020), PeerJ, DOI 10.7717/peerj.9867 2/14 and decreas (...truncated)