Investigating the cellular origin of rotator cuff muscle fatty infiltration and fibrosis after injury

Background: rotator cuff muscle atrophy, fibrosis and fatty infiltration are common complications after large and massive rotator cuff tears. Currently, there are no effective treatments for these muscle pathologies after injury. Furthermore, the cellular source for fibrotic and adipose tissues in rotator cuff muscle after injury remains unknown. In this study, we proposed that two groups of muscle resident progenitors, Tie2+ muscle mesenchymal progenitors and PDGFR alpha(+) fibro/adipogenic progenitor cells (FAPs), contribute significantly to rotator cuff muscle fibrosis and fatty infiltration. Methods: we tested our hypothesis using reporter mice. Rotator cuff muscles from Tie2-GFP and PDGFR alpha-GFP reporter mice were harvested at 2 and 6 weeks after unilateral massive rotator cuff tear surgeries. Immunofluorescent staining for fibroblast and adipocyte markers was conducted. Results: our results showed significant co-localization of Tie2+ cells with fibrotic markers vimentin and aSMA. In the PDGFR alpha-GFP reporter mice, GFP signal was seen in only a small fraction of cells staining positive for vimentin and aSMA. However, PDGFR alpha showed significant co-localization with adipocyte markers, including PPAR-gamma, adiponectin, and perilipin A. Oil red O staining confirmed that the mature adipocytes appearing in rotator cuff muscles after injury are also PDGFR alpha(+). Conclusion: these data demonstrated that the Tie2(+) muscle mesenchymal progenitors are the major source of fibroblasts while PDGFR alpha(+) FAPs are the major source of adipocytes in rotator cuff muscle fatty infiltration. Basic Science Study.