Role of distinct fibroblast lineages and immune cells in dermal repair following UV radiation induced tissue damage

  1. Emanuel Rognoni  Is a corresponding author
  2. Georgina Goss
  3. Toru Hiratsuka
  4. Kalle H Sipilä
  5. Thomas Kirk
  6. Katharina I Kober
  7. Prudence PokWai Lui
  8. Victoria SK Tsang
  9. Nathan J Hawkshaw
  10. Suzanne M Pilkington
  11. Inchul Cho
  12. Niwa Ali
  13. Lesley E Rhodes
  14. Fiona M Watt  Is a corresponding author
  1. Queen Mary University of London, United Kingdom
  2. King's College London, United Kingdom
  3. German Cancer Research Center (DKFZ), Germany
  4. The University of Manchester and Salford Royal NHS Foundation Trust, United Kingdom

Abstract

Solar ultraviolet radiation (UVR) is a major source of skin damage, resulting in inflammation, premature ageing and cancer. While several UVR-induced changes, including extracellular matrix reorganisation and epidermal DNA damage, have been documented, the role of different fibroblast lineages and their communication with immune cells has not been explored. We show that acute and chronic UVR exposure led to selective loss of fibroblasts from the upper dermis in human and mouse skin. Lineage tracing and in vivo live imaging revealed that repair following acute UVR is predominantly mediated by papillary fibroblast proliferation and fibroblast reorganisation occurs with minimal migration. In contrast, chronic UVR exposure led to a permanent loss of papillary fibroblasts, with expansion of fibroblast membrane protrusions partially compensating for the reduction in cell number. Although UVR strongly activated Wnt-signalling in skin, stimulation of fibroblast proliferation by epidermal b-catenin stabilisation did not enhance papillary dermis repair. Acute UVR triggered an infiltrate of neutrophils and T cell subpopulations and increased pro-inflammatory prostaglandin signalling in skin. Depletion of CD4 and CD8 positive cells resulted in increased papillary fibroblast depletion, which correlated with an increase in DNA damage, pro-inflammatory prostaglandins and reduction in fibroblast proliferation. Conversely, topical COX-2 inhibition prevented fibroblast depletion and neutrophil infiltration after UVR. We conclude that loss of papillary fibroblasts is primarily induced by a deregulated inflammatory response, with infiltrating T cells supporting fibroblast survival upon UVR-induced environmental stress.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source Data files containing the numerical data used to generate the figures have been provided for all figures.

The following previously published data sets were used

Article and author information

Author details

  1. Emanuel Rognoni

    Centre for Endocrinology, Queen Mary University of London, London, United Kingdom
    For correspondence
    e.rognoni@qmul.ac.uk
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6050-2860
  2. Georgina Goss

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  3. Toru Hiratsuka

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5359-2690
  4. Kalle H Sipilä

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  5. Thomas Kirk

    Centre for Endocrinology, Queen Mary University of London, London, United Kingdom
    Competing interests
    No competing interests declared.
  6. Katharina I Kober

    Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ), Heidelberg, Germany
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8076-3379
  7. Prudence PokWai Lui

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  8. Victoria SK Tsang

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  9. Nathan J Hawkshaw

    Division of Musculoskeletal and Dermatological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester, United Kingdom
    Competing interests
    No competing interests declared.
  10. Suzanne M Pilkington

    Division of Musculoskeletal and Dermatological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester, United Kingdom
    Competing interests
    No competing interests declared.
  11. Inchul Cho

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5527-0962
  12. Niwa Ali

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4473-8747
  13. Lesley E Rhodes

    Division of Musculoskeletal and Dermatological Sciences, The University of Manchester and Salford Royal NHS Foundation Trust, Manchester, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9107-6654
  14. Fiona M Watt

    Centre for Stem Cells and Regenerative Medicine, King's College London, London, United Kingdom
    For correspondence
    fiona.watt@kcl.ac.uk
    Competing interests
    Fiona M Watt, FW is on secondment as Executive Chair of the Medical Research Council. The author has no other competing interests to declare..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9151-5154

Funding

Cancer Research UK (C219/A23522)

  • Fiona M Watt

Medical Research Council (MR/PO18823/1)

  • Fiona M Watt

Wellcome Trust (206439/Z/17/Z)

  • Fiona M Watt

Wellcome Trust (WT94028)

  • Lesley E Rhodes

NIHR Greater Manchester Patient Safety Translational Research Centre

  • Nathan J Hawkshaw
  • Lesley E Rhodes

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Edward E Morrisey, University of Pennsylvania, United States

Ethics

Animal experimentation: All animal experiments were subject to local ethical approval and performed under the terms of a UKgovernment Home Office license (PPL 70/8474 or PP0313918).

Human subjects: Ethical approval was granted by the Greater Manchester North NHS research ethics committee (ref:11/NW/0567) for the studies presented in Figure 1 and Figure 6. Details of the time course analysis of UVRchallenged human skin have been reported previously (Hawkshaw NJ et al. 2020). All volunteers provided written informed consent in accordance with the Declaration of Helsinki principles.

Version history

  1. Received: June 8, 2021
  2. Accepted: December 22, 2021
  3. Accepted Manuscript published: December 23, 2021 (version 1)
  4. Version of Record published: January 10, 2022 (version 2)

Copyright

© 2021, Rognoni et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Emanuel Rognoni
  2. Georgina Goss
  3. Toru Hiratsuka
  4. Kalle H Sipilä
  5. Thomas Kirk
  6. Katharina I Kober
  7. Prudence PokWai Lui
  8. Victoria SK Tsang
  9. Nathan J Hawkshaw
  10. Suzanne M Pilkington
  11. Inchul Cho
  12. Niwa Ali
  13. Lesley E Rhodes
  14. Fiona M Watt
(2021)
Role of distinct fibroblast lineages and immune cells in dermal repair following UV radiation induced tissue damage
eLife 10:e71052.
https://doi.org/10.7554/eLife.71052

Share this article

https://doi.org/10.7554/eLife.71052

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