Skip to main content

Advertisement

SpringerLink
Log in

Dermal white adipose tissue undergoes major morphological changes during the spontaneous and induced murine hair follicle cycling: a reappraisal

  • Original Paper
  • Published:
Archives of Dermatological Research Aims and scope Submit manuscript

Abstract

In murine skin, dermal white adipose tissue (DWAT) undergoes major changes in thickness in synchrony with the hair cycle (HC); however, the underlying mechanisms remain unclear. We sought to elucidate whether increased DWAT thickness during anagen is mediated by adipocyte hypertrophy or adipogenesis, and whether lipolysis or apoptosis can explain the decreased DWAT thickness during catagen. In addition, we compared HC-associated DWAT changes between spontaneous and depilation-induced hair follicle (HF) cycling to distinguish between spontaneous and HF trauma-induced events. We show that HC-dependent DWAT remodelling is not an artefact caused by fluctuations in HF down-growth, and that dermal adipocyte (DA) proliferation and hypertrophy are HC-dependent, while classical DA apoptosis is absent. However, none of these changes plausibly accounts for HC-dependent oscillations in DWAT thickness. Contrary to previous studies, in vivo BODIPY uptake suggests that increased DWAT thickness during anagen occurs via hypertrophy rather than hyperplasia. From immunohistomorphometry, DWAT thickness likely undergoes thinning during catagen by lipolysis. Hence, we postulate that progressive, lipogenesis-driven DA hypertrophy followed by dynamic switches between lipogenesis and lipolysis underlie DWAT fluctuations in the spontaneous HC, and dismiss apoptosis as a mechanism of DWAT reduction. Moreover, the depilation-induced HC displays increased DWAT thickness, area, and DA number, but decreased DA volume/area compared to the spontaneous HC. Thus, DWAT shows additional, novel HF wounding-related responses during the induced HC. This systematic reappraisal provides important pointers for subsequent functional and mechanistic studies, and introduces the depilation-induced murine HC as a model for dissecting HF–DWAT interactions under conditions of wounding/stress.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Ali N, Zirak B, Rodriguez RS et al (2017) Regulatory T cells in skin facilitate epithelial stem cell differentiation. Cell 169:1119–1129

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Al-Nuaimi Y, Goodfellow M, Paus R, Baier G (2012) A prototypic mathematical model of the human hair cycle. J Theor Biol 310:143–159

    Article  PubMed  Google Scholar 

  3. Ansell DM, Kloepper JE, Thomason HA et al (2011) Exploring the “hair growth-wound healing connection”: anagen phase promotes wound re-epithelialization. J Invest Dermatol 131:518–528

    Article  PubMed  CAS  Google Scholar 

  4. Bassino E, Gasparri F, Giannini V, Munaron L (2015) Paracrine crosstalk between human hair follicle dermal papilla cells and microvascular endothelial cells. Exp Dermatol 24:388–390

    Article  PubMed  CAS  Google Scholar 

  5. Bernard BA (2017) The hair follicle enigma. Exp Dermatol 26:472–477

    Article  PubMed  Google Scholar 

  6. Butcher E (1934) The hair cycles in the albino rat. Anat Rec 61:5–19

    Article  Google Scholar 

  7. Castellana D, Paus R, Perez-Moreno M (2014) Macrophages contribute to the cyclic activation of adult hair follicle stem cells. PLoS Biol 12:e1002002

    Article  PubMed  PubMed Central  Google Scholar 

  8. Chase HB, Montagna W, Malone JD (1953) Changes in the skin in relation to the hair growth cycle. Anat Rec 116:75–81

    Article  PubMed  CAS  Google Scholar 

  9. Chen CC, Plikus MV, Tang PC et al (2016) The modulatable stem cell niche: tissue interactions during hair and feather follicle regeneration. J Mol Biol 428:1423–1440

    Article  PubMed  CAS  Google Scholar 

  10. Donati G, Proserpio V, Lichtenberger BM et al (2014) Epidermal Wnt/β-catenin signaling regulates adipocyte differentiation via secretion of adipogenic factors. Proc Natl Acad Sci USA 111:E1501–E1509

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Driskell RR, Jahoda CAB, Chuong C-M et al (2014) Defining dermal adipose tissue. Exp Dermatol 23:629–631

    Article  PubMed  PubMed Central  Google Scholar 

  12. Driskell RR, Lichtenberger BM, Hoste E et al (2013) Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature 504:277–281

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Dry FW (1926) The coat of the mouse (Mus musculus). J Genet 16:287–340

    Article  Google Scholar 

  14. Ezure T, Amano S (2015) Increment of subcutaneous adipose tissue is associated with decrease of elastic fibres in the dermal layer. Exp Dermatol 24:924–929

    Article  PubMed  CAS  Google Scholar 

  15. Festa E, Fretz J, Berry R et al (2011) Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling. Cell 146:761–771

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Fu X, Fang L, Li H et al (2007) Adipose tissue extract enhances skin wound healing. Wound Repair Regen 15:540–548

    Article  PubMed  Google Scholar 

  17. Garten A, Schuster S, Kiess W (2012) The insulin-like growth factors in adipogenesis and obesity. Endocrinol Metab Clin N Am 41:283–295

    Article  CAS  Google Scholar 

  18. Geyfman M, Plikus MV, Treffeisen E et al (2015) Resting no more: re-defining telogen, the maintenance stage of the hair growth cycle. Biol Rev 90:1179–1196

    Article  PubMed  Google Scholar 

  19. Goldring MB, Goldring SR (1991) Cytokines and cell growth control. Crit Rev Eukaryot Gene Expr 1:301–326

    PubMed  CAS  Google Scholar 

  20. Gupta RK, Mepani RJ, Kleiner S et al (2012) Zfp423 expression identifies committed preadipocytes and localizes to adipose endothelial and perivascular cells. Cell Metab. https://doi.org/10.1016/j.cmet.2012.01.010

    Article  PubMed  PubMed Central  Google Scholar 

  21. Gurtner GC, Werner S, Barrandon Y, Longaker MT (2008) Wound repair and regeneration. Nature 453:314–321

    Article  PubMed  CAS  Google Scholar 

  22. Halberg N, Khan T, Trujillo ME et al (2009) Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol. https://doi.org/10.1128/MCB.00192-09

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hansen LS, Coggle JE, Wells J, Charles MW (1984) The influence of the hair cycle on the thickness of mouse skin. Anat Rec 210:569–573

    Article  PubMed  CAS  Google Scholar 

  24. Herold C, Rennekampff HO, Engeli S (2013) Apoptotic pathways in adipose tissue. Apoptosis 18:911–916

    Article  PubMed  CAS  Google Scholar 

  25. Horsley V, Watt F (2017) Repeal and replace: adipocyte regeneration in wound repair. Cell Stem Cell 20:424–426

    Article  PubMed  CAS  Google Scholar 

  26. Jimenez F, Poblet E, Izeta A (2015) Reflections on how wound healing-promoting effects of the hair follicle can be translated into clinical practice. Exp Dermatol 24:91–94

    Article  PubMed  Google Scholar 

  27. Jin Z, Du Y, Schwaid AG et al (2015) Maternal adiponectin controls milk composition to prevent neonatal inflammation. Endocrinology. https://doi.org/10.1210/en.2014-1738

    Article  PubMed Central  PubMed  Google Scholar 

  28. Kawai K, Kageyama A, Tsumano T et al (2008) Effects of adiponectin on growth and differentiation of human keratinocytes—implication of impaired wound healing in diabetes. Biochem Biophys Res Commun 374:269–273

    Article  PubMed  CAS  Google Scholar 

  29. Kloepper JE, Kawai K, Bertolini M et al (2013) Loss of γδ T cells results in hair cycling defects. J Invest Dermatol 133:1666–1669

    Article  PubMed  CAS  Google Scholar 

  30. Kroemer G, Galluzzi L, Vandenabeele P et al (2009) Classification of cell death. Cell Death Differ 16:3–11

    Article  PubMed  CAS  Google Scholar 

  31. Kruglikov IL, Scherer PE (2016) Dermal adipocytes and hair cycling: is spatial heterogeneity a characteristic feature of the dermal adipose tissue depot? Exp Dermatol 25:258–262

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Langan EA, Philpott MP, Kloepper JE, Paus R (2015) Human hair follicle organ culture: theory, application and perspectives. Exp Dermatol 24:903–911

    Article  PubMed  Google Scholar 

  33. Lindner G, Botchkarev V, Botchkareva NV et al (1997) Analysis of apoptosis during hair follicle regression (catagen). Am J Pathol 151:1601–1617

    PubMed  PubMed Central  CAS  Google Scholar 

  34. Mecklenburg L, Tobin DJ, Müller-Röver S et al (2000) Active hair growth (anagen) is associated with angiogenesis. J Invest Dermatol 114:909–916

    Article  PubMed  CAS  Google Scholar 

  35. Müller-Röver S, Handjiski B, van der Veen C et al (2001) A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J Invest Dermatol 117:3–15

    Article  PubMed  Google Scholar 

  36. Ohnemus U, Uenalan M, Inzunza J et al (2006) The hair follicle as an estrogen target and source. Endocr Rev 27:677–706

    Article  PubMed  CAS  Google Scholar 

  37. Paus R, Stenn KS, Link RE (1990) Telogen skin contains an inhibitor of hair growth. Br J Dermatol 122:777–784

    Article  PubMed  CAS  Google Scholar 

  38. Paus R, Handjiski B, Czarnetzki BM, Eichmuller S (1994) A murine model for inducing and manipulating hair follicle regression (catagen): effects of dexamethasone and cyclosporin A. J Invest Dermatol 103:143–147

    Article  PubMed  CAS  Google Scholar 

  39. Paus R, Foitzik K (2004) In search of the “hair cycle clock”: a guided tour. Differentiation 72:489–511

    Article  PubMed  CAS  Google Scholar 

  40. Paus R, Maurer M, Slominski A, Czarnetzki BM (1994) Mast cell involvement in murine hair growth. Dev Biol 163:230–240

    Article  PubMed  CAS  Google Scholar 

  41. Paus R, van der Veen C, Eichmüller S et al (1998) Generation and cyclic remodeling of the hair follicle immune system in mice. J Invest Dermatol 111:7–18

    Article  PubMed  CAS  Google Scholar 

  42. Plikus MV, Chuong CM (2014) Macroenvironmental regulation of hair cycling and collective regenerative behavior. Cold Spring Harb Perspect Med 4:A015198

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Plikus MV, Guerrero-Juarez CF, Ito M et al (2017) Regeneration of fat cells from myofibroblasts during wound healing. Science 355(6326):748–752

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Plikus MV, Mayer JA, de la Cruz D et al (2008) Cyclic dermal BMP signalling regulates stem cell activation during hair regeneration. Nature 451:340–344

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Ramot Y, Mastrofrancesco A, Camera E et al (2015) The role of PPARγ-mediated signalling in skin biology and pathology: new targets and opportunities for clinical dermatology. Exp Dermatol 24:245–251

    Article  PubMed  CAS  Google Scholar 

  46. Rezza A, Sennett R, Tanguy M et al (2015) PDGF signalling in the dermis and in dermal condensates is dispensable for hair follicle induction and formation. Exp Dermatol 24:468–470

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Rivera-Gonzalez GC, Shook BA, Andrae J et al (2016) Skin adipocyte stem cell self-renewal is regulated by a PDGFA/AKT-signaling axis. Cell Stem Cell 19:738–751

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Rodeheffer MS, Birsoy K, Friedman JM (2008) Identification of white adipocyte progenitor cells in vivo. Cell 135:240–249

    Article  PubMed  CAS  Google Scholar 

  49. Rosen E, Spiegelman B (2000) Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol 16:145–171

    Article  PubMed  CAS  Google Scholar 

  50. Rutkowski JM, Stern JH, Scherer PE (2015) The cell biology of fat expansion. J Cell Biol. https://doi.org/10.1083/jcb.201409063

    Article  PubMed  PubMed Central  Google Scholar 

  51. Sardella C, Winkler C, Quignodon L et al (2017) Delayed hair follicle morphogenesis and hair follicle dystrophy in a lipoatrophy mouse model of pparg total deletion. J Invest Dermatol 138:500–510. https://doi.org/10.1016/j.jid.2017.09.024

    Article  PubMed  CAS  Google Scholar 

  52. Schmidt BA, Horsley V (2013) Intradermal adipocytes mediate fibroblast recruitment during skin wound healing. Development 140:1517–1527

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Schmidt B, Horsley V (2012) Unravelling hair follicle-adipocyte communication. Exp Dermatol 21:827–830

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Schneider MR (2014) Coming home at last: dermal white adipose tissue. Exp Dermatol 23:634–635

    Article  PubMed  Google Scholar 

  55. Schneider MR, Schmidt-Ullrich R, Paus R (2009) The hair follicle as a dynamic miniorgan. Curr Biol 19:R132-142

    Article  CAS  Google Scholar 

  56. Seo G, Oh E, Yun M et al (2015) Adipose-derived stem cell conditioned medium accelerates keratinocyte differentiation via the upregulation of miR-24. Exp Dermatol 24:792–793

    Article  PubMed  Google Scholar 

  57. Shook B, Rivera Gonzalez G, Ebmeier S et al (2016) The role of adipocytes in tissue regeneration and stem cell niches. Annu Rev Cell Dev Biol 32:609–631

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Siersbæk R, Nielsen R, Mandrup S (2010) PPARγ in adipocyte differentiation and metabolism—novel insights from genome-wide studies. FEBS Lett. https://doi.org/10.1016/j.febslet.2010.06.010

    Article  PubMed  Google Scholar 

  59. Spiegelman BM, Hu E, Kim JB, Brun R (1997) PPARγ and the control of adipogenesis. Biochimie. https://doi.org/10.1016/S0300-9084(97)81500-3

    Article  PubMed  Google Scholar 

  60. Stenn KS, Paus R (2001) Controls of hair follicle cycling. Physiol Rev 81:449–494

    Article  PubMed  CAS  Google Scholar 

  61. Tang W, Zeve D, Suh JM et al (2008) White fat progenitor cells reside in the adipose vasculature. Science 322(5901):583–586

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Tao H, Umek RM (2000) C/EBPa is required to maintain postmitotic growth arrest in adipocytes. DNA Cell Biol 19:9–18

    Article  PubMed  CAS  Google Scholar 

  63. Wang Q, Tao C, Gupta RK, Scherer PE (2013) Tracking adipogenesis during white adipose tissue development, expansion and regeneration. Nat Med 19:1338–1344. https://doi.org/10.1038/nm.3324

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Weger N, Schlake T (2005) IGF-I signalling controls the hair growth cycle and the differentiation of hair shafts. J Invest Dermatol 125:873–882

    Article  PubMed  CAS  Google Scholar 

  65. Wojciechowicz K, Gledhill K, Ambler C et al (2013) Development of the mouse dermal adipose layer occurs independently of subcutaneous adipose tissue and is marked by restricted early expression of FABP4. PLoS One 8:e59811

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Won CH, Yoo HG, Park KY et al (2012) Hair growth-promoting effects of adiponectin in vitro. J Invest Dermatol 132:2849–2851

    Article  PubMed  CAS  Google Scholar 

  67. Yang C-C, Sheu H-M, Chung P-L et al (2015) Leptin of dermal adipose tissue is differentially expressed during the hair cycle and contributes to adipocyte-mediated growth inhibition of anagen-phase vibrissa hair. Exp Dermatol 24:57–60

    Article  PubMed  CAS  Google Scholar 

  68. Zeve D, Tang W, Graff J (2009) Fighting fat with fat: the expanding field of adipose stem cells. Cell Stem Cell. https://doi.org/10.1016/j.stem.2009.10.014

    Article  PubMed  PubMed Central  Google Scholar 

  69. Zhang B, Tsai PC, Gonzalez-Celeiro M et al (2016) Hair follicles’ transit-amplifying cells govern concurrent dermal adipocyte production through sonic hedgehog. Genes Dev 30:2325–2338

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

We thank the Plikus Lab, namely Prof Maksim Plikus and Raul Ramos (University of California, Irvine), for providing us with the tools and guidance to perform the in vivo BODIPY uptake experiment within their lab and for stimulating discussion and advice.

Funding

Supported in part by the NIHR Manchester Biomedical Research Centre (“Inflammatory Hair Diseases” Programme).

Author information

Authors and Affiliations

  1. Centre for Dermatology Research, The University of Manchester, Manchester, UK

    April R. Foster, Carina Nicu, Eleanor Hinde & Ralf Paus

  2. NIHR Manchester Biomedical Research Centre, and Manchester Academic Health Science Centre, Manchester, UK

    April R. Foster, Carina Nicu, Eleanor Hinde & Ralf Paus

  3. Institute of Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany

    Marlon R. Schneider

  4. Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

    Ralf Paus

Authors
  1. April R. Foster
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carina Nicu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marlon R. Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eleanor Hinde
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ralf Paus
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

AF performed most of the experiments. CN performed BODIPY and TUNEL experiments. AF, CN, and RP analysed the data. MRS contributed mouse skin samples. EH provided experimental advice and helped with data analysis. AF, CN, and RP wrote the manuscript, which was edited by all co-authors. RP conceived and supervised the study.

Corresponding author

Correspondence to Ralf Paus.

Ethics declarations

Conflict of interest

The authors have declared no conflicting interests.

Ethical approval

The spontaneous murine HC experiments were approved by the Committee on Animal Health and Care of the State of Upper Bavaria (Regierung von Oberbayern, Germany).

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Foster, A.R., Nicu, C., Schneider, M.R. et al. Dermal white adipose tissue undergoes major morphological changes during the spontaneous and induced murine hair follicle cycling: a reappraisal. Arch Dermatol Res 310, 453–462 (2018). https://doi.org/10.1007/s00403-018-1831-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00403-018-1831-y

Keywords

Search

Navigation