1. Stem Cells and Regenerative Medicine
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Cell non-autonomous functions of S100a4 drive fibrotic tendon healing

  1. Jessica E Ackerman
  2. Anne EC Nichols
  3. Valentina Studentsova
  4. Katherine T Best
  5. Emma Knapp
  6. Alayna E Loiselle  Is a corresponding author
  1. University of Rochester Medical Center, United States
Research Article
  • Cited 15
  • Views 7,253
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Cite this article as: eLife 2019;8:e45342 doi: 10.7554/eLife.45342

Abstract

Identification of pro-regenerative approaches to improve tendon healing is critically important as the fibrotic healing response impairs physical function. In the present study we tested the hypothesis that S100a4 haploinsufficiency or inhibition of S100a4 signaling improves tendon function following acute injury and surgical repair in a murine model. We demonstrate that S100a4 drives fibrotic tendon healing primarily through a cell non-autonomous process, with S100a4 haploinsufficiency promoting regenerative tendon healing. Moreover, inhibition of S100a4 signaling via antagonism of its putative receptor, RAGE, also decreases scar formation. Mechanistically, S100a4 haploinsufficiency decreases myofibroblast and macrophage content at the site of injury, with both cell populations being key drivers of fibrotic progression. Moreover, S100a4-lineage cells become α-SMA+ myofibroblasts, via loss of S100a4 expression. Using a combination of genetic mouse models, small molecule inhibitors and in vitro studies we have defined S100a4 as a novel, promising therapeutic candidate to improve tendon function after acute injury.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Jessica E Ackerman

    Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Anne EC Nichols

    Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Valentina Studentsova

    Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Katherine T Best

    Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Emma Knapp

    Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Alayna E Loiselle

    Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, United States
    For correspondence
    alayna_loiselle@urmc.rochester.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7548-6653

Funding

National Institute of Arthritis and Musculoskeletal and Skin Diseases (K01AR068386)

  • Alayna E Loiselle

National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR073169)

  • Alayna E Loiselle

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animal studies were approved by the University of Rochester Committee for Animal Resources (Protocol 2014-004).

Reviewing Editor

  1. Clifford J Rosen, Maine Medical Center Research Institute, United States

Publication history

  1. Received: January 18, 2019
  2. Accepted: May 23, 2019
  3. Accepted Manuscript published: May 24, 2019 (version 1)
  4. Version of Record published: June 3, 2019 (version 2)

Copyright

© 2019, Ackerman 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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