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Abstract Background The periodic growth of hair follicles is regulated by the balance of activators and inhibitors. The BMP signaling pathway plays an important role during hair follicle regeneration, but the exact BMP protein that controls this process has not been revealed. Methods The expression of BMP6 was determined via in situ hybridization and immunofluorescence. The in vivo effect of BMP6 overexpression was studied by using a previously established adenovirus injection model. The hair follicle regeneration was assessed by gross observation, H&E staining and 5-bromo-2-deoxyuridine (BrdU) tracing. The expression patterns of BMP6 signaling and Wnt10b signaling in both AdBMP6-treated and AdWnt10b-treated skins were determined by in situ hybridization and immunofluorescence. Results BMP6 was expressed differently in the stages of hair follicle cycle. The telogen-anagen transition of hair follicles was inhibited by adenovirus-mediated overexpression of BMP6. In the in vivo model, the BMP6 signaling was inhibited by Wnt10b and the Wnt10b signaling was inhibited by BMP6. The activation of hair follicle stem cells (HFSCs) was also competitively regulated by Wnt10b and BMP6. Conclusions Combined with previously reported data of Wnt10b, our findings indicate that BMP6 and Wnt10b are major inhibitors and activators respectively and their balance regulates the telogen-anagen transition of hair follicles. To the best of our knowledge, our data provide previously unreported insights into the regulation of hair follicle cycling and provide new clues for the diagnosis and therapies of hair loss.

Secreted Frizzled-related Protein 4 (sFRP4) belongs to Wnt inhibitors. Previously, we reported that sFRP4 inhibited the differentiation of melanocyte. Here, by using of immunostaining, we showed that sFRP4 is expressed in both human and mouse hair follicles, especially in the outer root sheath and inner root sheath. To reveal the role of sFRP4 in hair follicle growth and hair cycle, we induced synchronized hair cycle in the dorsal skin of mice by depilation, and injected sFRP4 intradermally into the skin. By hematoxylin and eosin staining, we found that the regeneration of hair follicles was inhibited by sFRP4. However, the structure of hair follicles remained complete. Compared with phosphate buffer saline-treated hair follicles, the sFRP4-treated hair follicles still had the same expression pattern of keratins. Our findings reveal that sFRP4 inhibits but not blocks the regeneration of hair follicles, and supply a potential therapeutic application to treat hair follicle regeneration disorders.

Following publication of the original article [1], the authors reported that they would like to correct the second last sentence of “Authors’ information” section as PW is an undergraduate, but was incorrectly described as a Ph.D. in the sentence. The sentence should read “PW is an undergraduate. YZ, YX, WX, HG, FD and YL are Ph.D.”. The authors sincerely apologize for having this unintentional error in the article, and apologize for any inconvenience caused.

Dermal papilla (DP) plays important roles in hair follicle regeneration. Long-term culture of mouse DP cells can provide enough cells for research and application of DP cells. We optimized the culture strategy for DP cells from three dimensions: stepwise dissection, collagen I coating, and optimized culture medium. Based on the optimized culture strategy, we immortalized primary DP cells with SV40 large T antigen, and established several immortalized DP cell strains. By comparing molecular expression and morphologic characteristics with primary DP cells, we found one cell strain named iDP6 was similar with primary DP cells. Further identifications illustrate that iDP6 expresses FGF7 and α-SMA, and has activity of alkaline phosphatase. During the process of characterization of immortalized DP cell strains, we also found that cells in DP were heterogeneous. We successfully optimized culture strategy for DP cells, and established an immortalized DP cell strain suitable for research and application of DP cells.

Wnt signaling plays crucial role in regulating melanocyte stem cells/melanocyte differentiation in the hair follicle. However, how the Wnt signaling is balanced to be overactivated to control follicular melanocytes behavior remains unknown. Here, by using immunofluorescence staining, we showed that secreted frizzled-related protein 4 (sFRP4) is preferentially expressed in the skin epidermal cells rather than in melanocytes. By overexpression of sFRP4 in skin cells in vivo and in vitro, we found that sFRP4 attenuates activation of Wnt signaling, resulting in decrease of melanocytes differentiation in the regenerating hair follicle. Our findings unveiled a new regulator that involves modulating melanocytes differentiation through a paracrine mechanism in hair follicle, supplying a hope for potential therapeutic application to treat skin pigmentation disorders.