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Adenovirus-Mediated Wnt10b Overexpression Induces Hair

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Adenovirus-Mediated Wnt10b Overexpression Induces Hair ORIGINAL ARTICLE See related commentary on pg 7 Adenovirus-Mediated Wnt10b Overexpression Induces Hair Follicle Regeneration Yu-Hong Li1, Kun Zhang1, Ke Yang1, Ji-Xing Ye2, Yi-Zhan Xing1, Hai-Ying Guo1, Fang Deng1, Xiao-Hua Lian1 and Tian Yang1 Hair follicles periodically undergo regeneration. The balance between activators and inhibitors may determine the time required for telogen hair follicles to reenter anagen. We previously reported that Wnt10b (wingless- type mouse mammary tumor virus integration site family member 10b) could promote the growth of hair follicles in vitro. To unveil the roles of Wnt10b in hair follicle regeneration, we established an in vivo mouse model using intradermal injection. On the basis of this model, we found that Wnt10b could induce the biological switch of hair follicles from telogen to anagen when overexpressed in the skin. The induced hair follicles expressed structure markers and could cycle normally into catagen. Conversely, anagen onset was abrogated by the knockdown of Wnt10b with small interfering RNA (siRNA). The Wnt10b aberrant expression data suggest that it is one of the activators of hair follicle regeneration. The b-catenin protein is translocated to the nucleus in Wnt10b-induced hair follicles. The biological effects of Wnt10b were abrogated when b-catenin expression was downregulated with siRNA. These data revealed that Wnt10b might induce hair follicle regeneration in vivo via the enhanced activation of the canonical Wnt signaling pathway. To our knowledge, our data provide previously unreported insights into the regulation of hair follicle cycling and provide potential therapeutic targets for hair follicle–related diseases. Journal of Investigative Dermatology (2013) 133, 42–48; doi:10.1038/jid.2012.235; published online 26 July 2012 INTRODUCTION Research on the regulation of the hair follicle cycle The hair follicle is a specific mini-organ appendage of the is important and urgently needed. Many signaling pathways skin. Postnatal follicles have characteristic periodic growth are involved in the hair follicle cycle, such as the Wnt stages, namely the anagen, catagen, and telogen stages. (wingless-type mouse mammary tumor virus integration site ), The hair follicle can reenter anagen with certain stimuli in bone morphogenetic protein, fibroblast growth factor, and the telogen stage and thus continue the hair follicle cycle. Sonic hedgehog pathways (Kawano et al., 2005; Rendl et al., The process of the hair follicle reentering anagen is termed 2008; Alvarez-Medina et al., 2009). The Wnt signaling hair follicle regeneration (Alonso and Fuchs, 2006). Because pathway has an important role in hair follicle morphogenesis of its ability to undergo periodic growth, the hair follicle is an and regeneration (Andl et al., 2002). Usually, the Wnt effective model for tissue regeneration research. Hair follicles signaling pathway is divided into a canonical pathway and not only produce hair but are also associated with skin a noncanonical pathway. More attention is paid to the regeneration, pilomatricoma, and basal cell carcinoma canonical pathway, and its signal chain is better elucidated. (Kruger et al., 1999). If the hair follicle cycle is interrupted, Canonical Wnt signals are transduced through the Frizzled hair follicle–related diseases, such as androgenic alopecia, family receptors and coreceptors to the b-catenin signaling might occur (McDonough and Schwartz, 2011). Much cascade. When b-catenin accumulates in the cytoplasm, research is still needed to understand how to solve these it can be translocated to the nucleus, where it interacts with problems. the transcription factors TCF/LEF to regulate the expressions of target genes (Katoh, 2007). Hair follicle morphogenesis and regeneration would be significantly impacted if any 1 Department of Cell Biology, The Third Military Medical University, molecule in the canonical signal chain was blocked (Andl Chongqing, China and 2Bioengineering College of Chongqing University, Chongqing, China et al., 2002). Correspondence: Xiao-Hua Lian or Tian Yang, Department of Cell Biology, We previously showed that Wnt10b (Wnt family member The Third Military Medical University, Gaotanyan Street Number 30, 10b) could promote the growth of hair follicles in vitro, Shapingba, Chongqing 400038, China. E-mail: [email protected] or probably via a canonical Wnt signaling pathway (Li et al., [email protected] 2011). Reddy et al. (2001) reported that Wnt10b was Abbreviations: siRNA, small interfering RNA; Wnt10b, wingless-type highly and specifically expressed in the placode of the mouse mammary tumor virus integration site family member 10b; X-gal, 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside epidermis in hair follicle morphogenesis. Ouji et al. (2007, Received 19 August 2011; revised 26 May 2012; accepted 7 June 2012; 2008 also reported that Wnt10b might promote published online 26 July 2012 epithelial differentiation and shaft growth). However, the 42 Journal of Investigative Dermatology (2013), Volume 133 & 2013 The Society for Investigative Dermatology Y-H Li et al. Wnt10b Induces Hair Follicle Regeneration in vivo effects of Wnt10b on the hair follicle cycle are still a Wnt10b d Wnt10b/DAPI unknown. DP It was recently reported that in late telogen, the balance between activators and inhibitors may determine whether a DP hair follicle can reenter anagen (Plikus et al., 2011; Oshimori DP DP and Fuchs, 2012; Wang et al., 2012). Activators and inhibitors may be of intrafollicular or extrafollicular origin, Anagen Anagen whereas stem cells will sum them up (Chen and Chuong, be 2012). Thus, the increase in the quantity of activators in late Wnt10b Wnt10b/DAPI telogen may induce hair follicle regeneration. From the literature and our previous report, we infer that Wnt10b may be one of these activators of hair follicle regeneration. To test this hypothesis, we established an in vivo experimental DP model to study hair follicle changes caused by the over- Catagen Catagen expression or suppression of Wnt10b. On the basis of this model, we studied the signaling pathway that Wnt10b cf Wnt10b Wnt10b/DAPI mediates during this process. We found that Wnt10b could induce the biological switch of hair follicles from telogen to anagen. In addition, we show that Wnt10b might signal through the Wnt/b-catenin signaling pathway in vivo. To our knowledge, our data provide previously unreported evidence DP Telogen demonstrating that Wnt10b is one of the regulators under- Telogen DP lying hair follicle cycling. Figure 1. The expression pattern of Wnt10b (wingless-type mouse mammary tumor virus integration site family member 10b) throughout RESULTS the hair follicle cycle. The expression pattern of Wnt10b in the dorsal skin Wnt10b is periodically expressed in the hair follicle cycle of C57 mice was determined by in situ hybridization (a–c) and immuno- The normal expression of Wnt10b in the hair follicle cycle fluorescence (d–f). Wnt10b was expressed in anagen (a, d) but not in catagen was determined by both immunofluorescence and in situ (b, e) or telogen (c, f). The upper right corner shows a magnification of the hybridization (Figure 1). Wnt10b was expressed in anagen framed labeled area. The dashed line delineates the hair follicle structure. hair follicles and was not expressed in catagen or telogen hair Arrowheads in a and d show the expression of Wnt10b in hair matrix follicles. In anagen, Wnt10b was expressed in hair matrix cells. DAPI, 4’,6-diamidino-2-phenylindole; DP, dermal papilla. Scale bar ¼ 10 mm. cells and the precortex cells in the lower part of hair follicles. Real-time PCR demonstrated that wnt10b expression began to increase either at the end of telogen or at the onset of At 24 hours after overexpression, Wnt10b was expressed anagen (Supplementary Figure S1 online). The characteristic in nearly all of the skin samples. Over time, the expres- expression pattern of Wnt10b suggests that it may be a critical sion became more restricted. At 72 hours after overexpres- protein in hair follicle regeneration. sion, the expression of Wnt10b was gradually restricted We constructed an adenovirus-mediated overexpression to the bulge area and hair bulb (Figure 2, Supplementary model to test this hypothesis. X-gal (5-bromo-4-chloro-3- Figure S4 online), especially the bulge area near the indolyl-beta-D-galactopyranoside) staining and fluorescence sebaceous gland. These results further verify that the in vivo microscopy were used to analyze the adenovirus-mediated model works well. injection model. X-gal staining revealed that the target gene was expressed in the injection area (causing the formation of Overexpressed Wnt10b induces hair follicle regeneration a wheal around the injection site) 24 hours after injection. After being treated with AdWnt10b, the telogen hair follicle Green fluorescence was observed in the AdWnt10b (Wnt10b proceeded into anagen earlier than expected (Figure 3a–d). mediated by adenovirus) injection area (Supplementary Fourteen days after the injection of 108 pfu mlÀ1 AdWnt10b, Figure S2 online). The mRNA expression of wnt10b increased the hair follicle regeneration ratio of the labeled area was by approximately 14-fold 24 hours after AdWnt10b injection 13:20 (65%). When the AdWnt10b titer was increased compared with control telogen skin. The expression level of to 109 pfu mlÀ1, this ratio increased to 4:5 (80%). Thus, mRNA decreased over time. Seventy-two hours after AdWnt10b had a dose-specific effect on the promotion of AdWnt10b injection, the expression level decreased to the regeneration. level observed in normal early anagen skin (Supplementary To estimate systematically the impact of Wnt10b on the Figures S3 and S1 online). These results indicate that this hair follicle cycle, the treated mice were subjected to both in vivo model can restrictively express target genes tempo- macroscopic and microscopic observation through hema- rally in the injection area. toxylin and eosin staining. Beginning on the ninth day after To confirm the validity of the adenovirus-mediated in vivo treatment, the skin at the injection site gradually turned from model, we determined both the mRNA and protein expres- pink to black.
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