Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Collagen XVII deficiency alters epidermal patterning

Laboratory Investigation volume 102, pages 581–588 (2022)Cite this article

Subjects

Abstract

Vertebrates exhibit patterned epidermis, exemplified by scales/interscales in mice tails and grooves/ridges on the human skin surface (microtopography). Although the role of spatiotemporal regulation of stem cells (SCs) has been implicated in this process, the mechanism underlying the development of such epidermal patterns is poorly understood. Here, we show that collagen XVII (COL17), a niche for epidermal SCs, helps stabilize epidermal patterns. Gene knockout and rescue experiments revealed that COL17 maintains the width of the murine tail scale epidermis independently of epidermal cell polarity. Skin regeneration after wounding was associated with slender scale epidermis, which was alleviated by overexpression of human COL17. COL17-negative skin in human junctional epidermolysis bullosa showed a distinct epidermal pattern from COL17-positive skin that resulted from revertant mosaicism. These results demonstrate that COL17 contributes to defining mouse tail scale shapes and human skin microtopography. Our study sheds light on the role of the SC niche in tissue pattern formation.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

Buy

All prices are NET prices.

Fig. 1: Slender tail scales of Col17a1−/− mice.
Fig. 2: Restoration of the scale shape in Col17a1−/− tail epidermis by human COL17 overexpression.
Fig. 3: Small, but not slender, tail scales of aPKCλ eKO mice.
Fig. 4: Expression of wound-induced keratins in Col17a1−/− tail epidermis.
Fig. 5: Slender tail scales after skin regeneration and COL17 transgenic rescue.
Fig. 6: Distinct epidermal patterns of COL17-positive and negative human skin.
Fig. 7: COL17-related epidermal patterning.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Natsuga, K. Epidermal barriers. Cold Spring Harb. Perspect. Med. 4, a018218 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  2. Moreci, R. S. & Lechler, T. Epidermal structure and differentiation. Curr. Biol. 30, R144–R149 (2020).

    CAS  PubMed  Article  Google Scholar 

  3. Natsuga, K., Watanabe, M., Nishie, W. & Shimizu, H. Life before and beyond blistering: the role of collagen XVII in epidermal physiology. Exp. Dermatol. 28, 1135–1141 (2019).

    CAS  PubMed  Article  Google Scholar 

  4. Watt, F. M. & Fujiwara, H. Cell-extracellular matrix interactions in normal and diseased skin. Cold Spring Harb. Perspect. Biol. 3, a005124 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  5. Brakebusch, C. et al. Skin and hair follicle integrity is crucially dependent on β1 integrin expression on keratinocytes. EMBO J. 19, 3990–4003 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. Niculescu, C. et al. Conditional ablation of integrin alpha-6 in mouse epidermis leads to skin fragility and inflammation. Eur. J. Cell Biol. 90, 270–277 (2011).

    CAS  PubMed  Article  Google Scholar 

  7. Watanabe, M. et al. Type XVII collagen coordinates proliferation in the interfollicular epidermis. Elife 6, e26635 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  8. Dekoninck, S. et al. Defining the design principles of skin epidermis postnatal growth. Cell 181, 604–620 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. Gomez, C. et al. The interfollicular epidermis of adult mouse tail comprises two distinct cell lineages that are differentially regulated by Wnt, Edaradd, and Lrig1. Stem Cell Rep. 1, 19–27 (2013).

    CAS  Article  Google Scholar 

  10. Sada, A. et al. Defining the cellular lineage hierarchy in the interfollicular epidermis of adult skin. Nat. Cell Biol. 18, 619–631 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Jones, P. H., Harper, S. & Watt, F. M. Stem cell patterning and fate in human epidermis. Cell 80, 83–93 (1995).

    CAS  PubMed  Article  Google Scholar 

  12. Kobayashi, Y. et al. Interplay between epidermal stem cell dynamics and dermal deformation. Npj Comput. Mater. 4, 1–9 (2018).

    Article  Google Scholar 

  13. Wang, S. et al. Single cell transcriptomics of human epidermis identifies basal stem cell transition states. Nat. Commun. 11, 1–14 (2020).

    Article  CAS  Google Scholar 

  14. López-Rovira, T., Silva-Vargas, V. & Watt, F. M. Different consequences of β1 integrin deletion in neonatal and adult mouse epidermis reveal a context-dependent role of integrins in regulating proliferation, differentiation, and intercellular communication. J. Investig. Dermatol. 125, 1215–1227 (2005).

    PubMed  Article  Google Scholar 

  15. Tanimura, S. et al. Hair follicle stem cells provide a functional niche for melanocyte stem cells. Cell Stem Cell 8, 177–187 (2011).

    CAS  PubMed  Article  Google Scholar 

  16. Matsumura, H. et al. Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis. Science 351, aad4395 (2016).

    PubMed  Article  CAS  Google Scholar 

  17. Liu, N. et al. Stem cell competition orchestrates skin homeostasis and ageing. Nature 568, 344–350 (2019).

    CAS  PubMed  Article  Google Scholar 

  18. Hirate, Y. et al. Polarity-dependent distribution of angiomotin localizes Hippo signaling in preimplantation embryos. Curr. Biol. 23, 1181–1194 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Nishie, W. et al. Humanization of autoantigen. Nat. Med. 13, 378–383 (2007).

    CAS  PubMed  Article  Google Scholar 

  20. Noguchi, N. et al. Atypical protein kinase C isoforms differentially regulate directional keratinocyte migration during wound healing. J. Dermatol. Sci. 93, 101–108 (2019).

    CAS  PubMed  Article  Google Scholar 

  21. Osada, S.-I. et al. Atypical protein kinase C isoform, aPKCλ, is essential for maintaining hair follicle stem cell quiescence. J. Investig. Dermatol. 135, 2584–2592 (2015).

    CAS  PubMed  Article  Google Scholar 

  22. Yuspa, S. H., Hawley-Nelson, P., Koehler, B. & Stanley, J. R. A survey of transformation markers in differentiating epidermal cell lines in culture. Cancer Res. 40, 4694–4703 (1980).

    CAS  PubMed  Google Scholar 

  23. Nakamura, H. et al. Analysis of the COL17A1 in non-Herlitz junctional epidermolysis bullosa and amelogenesis imperfecta. Int. J. Mol. Med. 18, 333–337 (2006).

    CAS  PubMed  Google Scholar 

  24. Yuen, W., Pas, H., Sinke, R. & Jonkman, M. Junctional epidermolysis bullosa of late onset explained by mutations in COL17A1. Br. J. Dermatol. 164, 1280–1284 (2011).

    CAS  PubMed  Article  Google Scholar 

  25. Nishimura, M. et al. Extracellular cleavage of collagen XVII is essential for correct cutaneous basement membrane formation. Hum. Mol. Genet. 25, 328–339 (2016).

    CAS  PubMed  Article  Google Scholar 

  26. Stouthamer, A., Nieboer, C., Van der Waal, R. & Jonkman, M. Normal expression of the 19‐DEJ‐1 epitope in two siblings with late‐onset junctional epidermolysis bullosa. Br. J. Dermatol. 144, 1054–1057 (2001).

    CAS  PubMed  Article  Google Scholar 

  27. Okada, M., Sumino, Y., Ito, H. & Kitahata, H. Spontaneous deformation and fission of oil droplets on an aqueous surfactant solution. Phys. Rev. E 102, 042603 (2020).

    CAS  PubMed  Article  Google Scholar 

  28. Niessen, M. T. et al. aPKCλ controls epidermal homeostasis and stem cell fate through regulation of division orientation. J. Cell Biol. 202, 887–900 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Helfrich, I. et al. Role of aPKC isoforms and their binding partners Par3 and Par6 in epidermal barrier formation. J. Investig. Dermatol. 127, 782–791 (2007).

    CAS  PubMed  Article  Google Scholar 

  30. Watanabe, M. et al. Type XVII collagen interacts with the aPKC‐PAR complex and maintains epidermal cell polarity. Exp. Dermatol. 30, 62–67 (2021).

    CAS  PubMed  Article  Google Scholar 

  31. McGrath, J. A. et al. Mutations in the 180–kD bullous pemphigoid antigen (BPAG2), a hemidesmosomal transmembrane collagen (COL17A1), in generalized atrophic benign epidermolysis bullosa. Nat. Genet. 11, 83–86 (1995).

    CAS  PubMed  Article  Google Scholar 

  32. Jonkman, M. F. & Pasmooij, A. M. Revertant mosaicism—patchwork in the skin. N. Engl. J. Med. 360, 1680–1682 (2009).

    CAS  PubMed  Article  Google Scholar 

  33. Nomura, T. Recombination-induced revertant mosaicism in ichthyosis with confetti and loricrin keratoderma. J. Dermatol. Sci. 97, 94–100 (2020).

    CAS  PubMed  Article  Google Scholar 

  34. Hopkinson, S. B. & Jones, J. C. The N terminus of the transmembrane protein BP180 interacts with the N-terminal domain of BP230, thereby mediating keratin cytoskeleton anchorage to the cell surface at the site of the hemidesmosome. Mol. Biol. Cell. 11, 277–286 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. Koster, J., Geerts, D., Favre, B., Borradori, L. & Sonnenberg, A. Analysis of the interactions between BP180, BP230, plectin and the integrin α6β4 important for hemidesmosome assembly. J. Cell Sci. 116, 387–399 (2003).

    CAS  PubMed  Article  Google Scholar 

  36. Hopkinson, S. B., Baker, S. E. & Jones, J. Molecular genetic studies of a human epidermal autoantigen (the 180-kD bullous pemphigoid antigen/BP180): identification of functionally important sequences within the BP180 molecule and evidence for an interaction between BP180 and alpha 6 integrin. J. Cell Biol. 130, 117–125 (1995).

    CAS  PubMed  Article  Google Scholar 

  37. Aho, S. & Uitto, J. Direct interaction between the intracellular domains of bullous pemphigoid antigen 2 (BP180) and β4 integrin, hemidesmosomal components of basal keratinocytes. Biochem. Biophys. Res. Commun. 243, 694–699 (1998).

    CAS  PubMed  Article  Google Scholar 

  38. Schaapveld, R. Q. et al. Hemidesmosome formation is initiated by the β4 integrin subunit, requires complex formation of β4 and HD1/plectin, and involves a direct interaction between β4 and the bullous pemphigoid antigen 180. J. Cell. Biol. 142, 271–284 (1998).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. Hamill, K. J., Hopkinson, S. B., Jonkman, M. F. & Jones, J. C. Type XVII collagen regulates lamellipod stability, cell motility, and signaling to Rac1 by targeting bullous pemphigoid antigen 1e to α6β4 integrin. J. Biol. Chem. 286, 26768–26780 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. Natsuga, K. et al. Loss of interaction between plectin and type XVII collagen results in epidermolysis bullosa simplex. Hum. Mutat. 38, 1666–1670 (2017).

    CAS  PubMed  Article  Google Scholar 

  41. Tasanen, K., Tunggal, L., Chometon, G., Bruckner-Tuderman, L. & Aumailley, M. Keratinocytes from patients lacking collagen XVII display a migratory phenotype. Am. J. Pathol. 164, 2027–2038 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. Nishie, W., Kiritsi, D., Nyström, A., Hofmann, S. C. & Bruckner-Tuderman, L. Dynamic interactions of epidermal collagen XVII with the extracellular matrix: laminin 332 as a major binding partner. Am. J. Pathol. 179, 829–837 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Kamaguchi, M. & Iwata, H. The diagnosis and blistering mechanisms of mucous membrane pemphigoid. Front. Immunol. 10, 34 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. Morrow, A., Underwood, J., Seldin, L., Hinnant, T. & Lechler, T. Regulated spindle orientation buffers tissue growth in the epidermis. Elife 8, e48482 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. Muroyama, A. & Lechler, T. Polarity and stratification of the epidermis. Semin. Cell Dev. Biol. 23, 890–896 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  46. Poulson, N. D. & Lechler, T. Asymmetric cell divisions in the epidermis. Int. Rev. Cell Mol. Biol. 295, 199–232 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Niessen, M. T., Iden, S. & Niessen, C. M. The in vivo function of mammalian cell and tissue polarity regulators–how to shape and maintain the epidermal barrier. J. Cell Sci. 125, 3501–3510 (2012).

    CAS  PubMed  Article  Google Scholar 

  48. Tellkamp, F., Vorhagen, S. & Niessen, C. M. Epidermal polarity genes in health and disease. Cold Spring Harb. Perspect. Med. 4, a015255 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. Vorhagen, S. & Niessen, C. M. Mammalian aPKC/Par polarity complex mediated regulation of epithelial division orientation and cell fate. Exp. Cell Res. 328, 296–302 (2014).

    CAS  PubMed  Article  Google Scholar 

  50. Byrd, K. M. et al. Heterogeneity within Stratified Epithelial Stem Cell Populations Maintains the Oral Mucosa in Response to Physiological Stress. Cell Stem Cell 25, 814–829 e816 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. Has, C. et al. Mild clinical phenotype of Kindler syndrome associated with late diagnosis and skin cancer. Dermatology 221, 309–312 (2010).

    CAS  PubMed  Article  Google Scholar 

  52. de Almeida, H. L. Jr, Isaacsson, H., Guarenti, I. M., e Silva, R. M. & de Castro, L. A. S. Images in dermatology. An. Bras. Dermatol. 90, 581–584 (2015).

    PubMed  Article  Google Scholar 

  53. Grada, A., Mervis, J. & Falanga, V. Research techniques made simple: animal models of wound healing. J. Investig. Dermatol. 138, 2095–2105. e2091 (2018).

    CAS  PubMed  Article  Google Scholar 

  54. Falanga, V. et al. Full‐thickness wounding of the mouse tail as a model for delayed wound healing: accelerated wound closure in Smad3 knock‐out mice. Wound Repair Regen. 12, 320–326 (2004).

    PubMed  Article  Google Scholar 

  55. Aragona, M. et al. Defining stem cell dynamics and migration during wound healing in mouse skin epidermis. Nat. Commun. 8, 1–14 (2017).

    Article  Google Scholar 

Download references

Acknowledgements

We thank Ms. Megumi Takehara for their technical assistance. We also thank Professor Kim B. Yancey for providing K14-hCOL17 transgenic mice.

Author contributions

Y.W. performed the experiments, analyzed the data, interpreted the results, and wrote the manuscript. H.Kitahata analyzed the data, interpreted the results, and wrote the manuscript. H.Kosumi, M.W., Y.F., S.T., S.I.O., T.H., and W.N. performed the experiments and analyzed the data. M.N. and H.S. interpreted the results and supervised the study. K.N. designed the experiments, analyzed the data, interpreted the results, wrote the manuscript and supervised the study.

Funding

This work was funded by AMED to K.N. (20ek0109380h0003), the Lydia O’Leary Memorial Pias Dermatological Foundation to W.N., JST CREST (JPMJCR15D2) to M.N., and Five-star Alliance in NJRC Master. & Dev to H.Kitahata/M.N.

Author information

Authors and Affiliations

  1. Department of Dermatology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan

    Yunan Wang, Hideyuki Kosumi, Mika Watanabe, Yu Fujimura, Shota Takashima, Wataru Nishie, Hiroshi Shimizu & Ken Natsuga

  2. Department of Physics, Graduate School of Science, Chiba University, Chiba, Japan

    Hiroyuki Kitahata

  3. Department of Life Sciences and Systems Biology, Molecular Biotechnology Centre, University of Turin, Turin, Italy

    Mika Watanabe

  4. Department of Dermatology, Nippon Medical School, Tokyo, Japan

    Shin-Ichi Osada

  5. Department of Molecular Biology, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Tomonori Hirose

  6. Research Institute for Electronic Science, Hokkaido University, Sapporo, Japan

    Masaharu Nagayama

Authors
  1. Yunan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroyuki Kitahata
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hideyuki Kosumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mika Watanabe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu Fujimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shota Takashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Shin-Ichi Osada
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Tomonori Hirose
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wataru Nishie
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Masaharu Nagayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Hiroshi Shimizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ken Natsuga
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ken Natsuga.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics Approval and consent to participate

The institutional review board of the Hokkaido University Graduate School of Medicine approved all human studies described above (ID: 13-043). The study was conducted according to the principles of the Declaration of Helsinki. The participant provided written informed consent.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, Y., Kitahata, H., Kosumi, H. et al. Collagen XVII deficiency alters epidermal patterning. Lab Invest 102, 581–588 (2022). https://doi.org/10.1038/s41374-022-00738-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41374-022-00738-2

Search

Advanced search

Quick links