Background and hypothesis: After massive tears, rotator cuff muscle often undergoes atrophy, fibrosis, and fatty degeneration. These changes can lead to high surgical failure rates and poor patient outcomes. The identity of the progenitor cells involved in these processes has not been fully elucidated. Platelet-derived growth factor receptor β (PDGFRβ) and platelet-derived growth factor receptor α (PDGFRα) have previously been recognized as markers of cells involved in muscle fibroadipogenesis. We hypothesized that PDGFRα expression identifies a fibroadipogenic subset of PDGFRβ+ progenitor cells that contribute to fibroadipogenesis of the rotator cuff.
Methods: We created massive rotator cuff tears in a transgenic strain of mice that allows PDGFRβ+ cells to be tracked via green fluorescent protein (GFP) fluorescence. We then harvested rotator cuff muscle tissues at multiple time points postoperatively and analyzed them for the presence and localization of GFP+ PDGFRβ+ PDGFRα+ cells. We cultured, induced, and treated these cells with the molecular inhibitor CWHM-12 to assess fibrosis inhibition.
Results: GFP+ PDGFRβ+ PDGFRα+ cells were present in rotator cuff muscle tissue and, after massive tears, localized to fibrotic and adipogenic tissues. The frequency of PDGFRβ+ PDGFRα+ cells increased at 5 days after massive cuff tears and decreased to basal levels within 2 weeks. PDGFRβ+ PDGFRα+ cells were highly adipogenic and significantly more fibrogenic than PDGFRβ+ PDGFRα- cells in vitro and localized to adipogenic and fibrotic tissues in vivo. Treatment with CWHM-12 significantly decreased fibrogenesis from PDGFRβ+ PDGFRα+ cells.
Conclusion: PDGFRβ+ PDGFRα+ cells directly contribute to fibrosis and fatty degeneration after massive rotator cuff tears in the mouse model. In addition, CWHM-12 treatment inhibits fibrogenesis from PDGFRβ+ PDGFRα+ cells in vitro. Clinically, perioperative PDGFRβ+ PDGFRα+ cell inhibition may limit rotator cuff tissue degeneration and, ultimately, improve surgical outcomes for massive rotator cuff tears.
Keywords: PDGFRα; PDGFRβ; Rotator cuff; fatty degeneration; fibroadipogenic progenitor cell; massive rotator cuff tear; rotator cuff repair.
Copyright © 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.