Cell non-autonomous functions of S100a4 drive fibrotic tendon healing
- University of Rochester Medical Center, United States
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.
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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).
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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Cell non-autonomous functions of S100a4 drive fibrotic tendon healing
eLife 8:e45342.
https://doi.org/10.7554/eLife.45342
