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Adiponectin negatively regulates pigmentation, Wnt/β-catenin and HGF/c-Met signalling within human scalp hair follicles ex vivo

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Abstract

Adiponectin reportedly stimulates proliferation and elongation of human scalp hair follicles (HFs) ex vivo. In the current study, we investigated how adiponectin oligomers produced by perifollicular dermal white adipose tissue (dWAT), a potent source of adiponectin isoforms, influence human HF proliferation and pigmentation. To do so, we treated microdissected, organ-cultured HFs in the presence or absence of dWAT with a recombinant human adiponectin oligomer mix, or inhibited dWAT-derived adiponectin using a neutralizing antibody. Multiplex qPCR (Fluidigm) revealed that adiponectin oligomers downregulated pigmentation genes KITLG, PMEL and TYRP1 and Wnt genes AXIN2, LEF1 and WNT10B. In situ hybridization showed that adiponectin downregulated AXIN2 and LEF1, and up-regulated DKK1 within the dermal papilla (DP), a highly unusual transcriptional profile for a putative hair growth-promoting agent. Adiponectin oligomers also downregulated protein expression of the HGF receptor c-Met within the matrix and DP. However, adiponectin did not alter hair matrix keratinocyte proliferation within 48 h ex vivo, irrespective of the presence/absence of dWAT; HF pigmentation (Masson-Fontana histochemistry, tyrosinase activity) was also unchanged. In contrast, neutralizing adiponectin isoforms within HF + dWAT increased proliferation, melanin content and tyrosinase activity but resulted in fewer melanocytes and melanocytic dendrites, as assessed by gp100 immunostaining. These seemingly contradictory effects suggest that adiponectin exerts complex effects upon human HF biology, likely in parallel with the pro-pigmentation effects of dWAT- and DP-derived HGF. Our data suggest that dWAT-derived ratios of adiponectin isoforms and the cleaved, globular version of adiponectin may in fact determine how adiponectin impacts upon follicular pigmentation and growth.

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Acknowledgements

Magda Sawicka (Unilever, Colworth) for the Fluidigm experiment, Fei-Ling Lim (Unilever, Colworth) for IPA® analysis and Ranjit Bhogal (Unilever, Colworth). We also thank the Bioimaging Core Facility (University of Manchester) for their snapshot imaging equipment and Derek Pye for help with daily lab activities.

Funding

Biotechnology and Biological Science Research Council (BBSRC) iCASE Studentship (awardees: R.P., J.P., recipient: C.N.), co-funded by Unilever, Colworth, UK; NIHR Manchester Biomedical Research Centre, Inflammatory Hair Diseases Programme (Lead: R.P.), University of Miami start-up funds (R.P.), and Frost Endowed Scholarship to R.P. (Dept. of Dermatology).

Author information

Authors and Affiliations

  1. Centre for Dermatology Research, University of Manchester, Manchester and NIHR Manchester Biomedical Research Centre, Manchester, UK

    Carina Nicu, Jennifer Jackson, David Ansell & Ralf Paus

  2. Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

    Carina Nicu & Ralf Paus

  3. Crown Clinic, Manchester, UK

    Asim Shahmalak

  4. Unilever R&D Colworth, Colworth Science Park, Bedford, UK

    Jenny Pople

  5. Centre for Skin Sciences, Faculty of Life Sciences, University of Bradford, Bradford, UK

    David Ansell

  6. Monasterium Laboratory, Münster, Germany

    Ralf Paus

Authors
  1. Carina Nicu
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  2. Jennifer Jackson
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  3. Asim Shahmalak
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  4. Jenny Pople
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  5. David Ansell
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Contributions

C.N and R.P designed the experiments, which C.N and J.J. ran. A.S. provided hair samples for the study. C.N., J.P., D.M.A. and R.P. interpreted the data, and R.P. supervised the project. C.N. and R.P. wrote the manuscript, which was edited by all co-authors.

Corresponding author

Correspondence to Carina Nicu.

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Conflict of interest

No conflicts of interest to declare; for the record, R.P. is the founder and CEO of Monasterium Laboratory, Münster, Germany, and J.P. is an employee of Unilever Plc.

Ethical approval

Approval for tissue use granted by the Manchester Skin Health Biobank (19/NW/0082).

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Supplementary file2. Online Resource 1. Adiponectin oligomers do not affect keratinocyte proliferation, hair shaft differentiation or follicular pigmentation following 48 h cultures of dissected HFs. (a) ISH for ADIPOQ on control scalp skin clearly showed that perifollicular mature dermal adipocytes are the only source of adiponectin within dWAT. (b,c) Ki-67 staining revealed insignificantly lower levels of proliferation [p = 0.0843] and (d) no effect upon DP stalk fibroblasts [p = 0.1978]. (e,f) Similarly, K85 staining showed no difference in the amount of hair shaft differentiation within the pre-cortex following treatment with Acrp30 [p = 0.4295]. (g) The action of Acrp30 upon human HFs was validated using qPCR which showed upregulation of ADIPOR1 [p = 0.0932] and ADIPOR2 [p = 0.1341]. Pigmentation was also not modulated by Acrp30, as observed with (h,i) Masson Fontana [p =] and (k,l) gp100 stains [p = 0.9253], with no differences present in terms of (j) melanocyte number or (m) dendricity [all p values > 0.05]. n = 3 donors with 2–5 HFs analysed per donor per condition. 2-WAY ANOVA with multiple comparisons for (a). Unpaired (parametric) T-test for (d), (e), (g), (j), (m), (l). Mann–Whitney (nonparametric) U-test for (h). One-Way ANOVA test for (n).* P < 0.05 ** P < 0.01 *** P < 0.001. Scale bar = 50 μm across all images. Online Resource 2. Acrp30 has no effect upon keratinocyte proliferation or K15 levels within human HFs ex vivo. Treating dissected human HFs with increasing concentrations of recombinant Acrp30 oligomer mix had no effect upon proliferation within the hair bulb (a,b), or on expression levels of stem cell marker K15 (a,c), though K15 levels were slightly decreased following treatment with 5 μg/mL Acrp30 [all p-values > 0.05]. Similarly, Acrp30 did not modulate numbers of K15+ Ki-67+ cells across the HF other than within the hair bulb (a,d) following 1 μg/mL [p = 0.0664] and 5 μg/mL treatment [p = 0.0288]. n = 3 donors, 8–12 HFs per condition. * P < 0.05 ** P < 0.01 *** P < 0.001. Scale bar = 50 μm across all images. Online Resource 3. Acrp30 negatively modulates c-Met expression within both dissected HFs and HFs cultured with perifollicular dWAT, but has no effect upon HGF secretion. Acrp30 treatment resulted in downregulation of the HGF receptor c-Met (a) within both the hair matrix and DP fibroblasts of dissected HFs (b,c,) and tendentially in HF + dWAT (d,e) within the hair matrix [p = 0.2344] and dermal papilla [p = 0.1389]. However, Acrp30 did not affect levels of secreted HGF in either HF (f) or HF + dWAT cultures (g) [all p-values > 0.05]. n = 2 donors, 6HFs per condition for (b,c). n = 3 donors, 9 HFs per condition for (d) and (e). n = 3 donors for (f); n = 4 donors for (g). Unpaired (parametric) T-test for (c), (f); Mann–Whitney (nonparametric) U-test for (b); Kruskal–Wallis (nonparametric) test for (d), (e), One-Way ANOVA (parametric) for (g). Scale bar = 50 μm across all images. Online Resource 4. Acrp30 oligomer is predicted to downregulate key genes in the pigmentation pathway following 24-h ex vivo organ culture. Ingenuity® Pathway Analysis conducted on results from a multiplex qPCR (Fluidigm) revealed that Acrp30 was predicted to downregulate pigmentation genes such as SCF, MSH-R, MITF, TYR and TYRP1, and upregulate DCT, in dissected full-length human hair follicles. Online Resource 5. Acrp30 oligomer is predicted to inhibit the Wnt/β-catenin pathway following 24-h ex vivo organ culture. Ingenuity® Pathway Analysis conducted on results from a multiplex qPCR (Fluidigm) revealed that Acrp30 was predicted to downregulate Wnt/β-catenin genes such as LEF1, AXIN2, WNT6, WNT10B and various Frizzled receptors in dissected full-length human hair follicles, as well as up-regulating Wnt inhibitor DKK1. (PDF 751 KB)

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Nicu, C., Jackson, J., Shahmalak, A. et al. Adiponectin negatively regulates pigmentation, Wnt/β-catenin and HGF/c-Met signalling within human scalp hair follicles ex vivo. Arch Dermatol Res 315, 603–612 (2023). https://doi.org/10.1007/s00403-021-02291-2

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  • DOI: https://doi.org/10.1007/s00403-021-02291-2

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