Neer Award 2018: Platelet-derived growth factor receptor α co-expression typifies a subset of platelet-derived growth factor receptor β-positive progenitor cells that contribute to fatty degeneration and fibrosis of the murine rotator cuff

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 beta (PDGFR beta) and platelet-derived growth factor receptor alpha (PDGFR alpha) have previously been recognized as markers of cells involved in muscle fibroadipogenesis. We hypothesized that PDGFR alpha expression identifies a fibroadipogenic subset of PDGFR beta(+) 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 PDGFR beta(+) 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(+) PDGFR beta(+) PDGFR alpha(+) cells. We cultured, induced, and treated these cells with the molecular inhibitor CWHM-12 to assess fibrosis inhibition. Results: GFP(+) PDGFR beta(+) PDGFR alpha(+) cells were present in rotator cuff muscle tissue and, after massive tears, localized to fibrotic and adipogenic tissues. The frequency of PDGFR beta(+) PDGFR alpha(+) cells increased at 5 days after massive cuff tears and decreased to basal levels within 2 weeks. PDGFR beta(+) PDGFR alpha(+) cells were highly adipogenic and significantly more fibrogenic than PDGFR beta(+) PDGFR alpha-cells in vitro and localized to adipogenic and fibrotic tissues in vivo. Treatment with CWHM-12 significantly decreased fibrogenesis from PDGFR beta(+) PDGFR alpha(+) cells. Conclusion: PDGFR beta(+) PDGFR alpha(+) 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 PDGFR beta(+) PDGFR alpha(+) cells in vitro. Clinically, perioperative PDGFR beta(+) PDGFR alpha(+) cell inhibition may limit rotator cuff tissue degeneration and, ultimately, improve surgical outcomes for massive rotator cuff tears. (c) 2018 Journal of Shoulder and Elbow Surgery Board of Trustees. All rights reserved.