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

Abstract

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 PDGFRα + 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 PDGFRα-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 αSMA. In the PDGFRα-GFP reporter mice, GFP signal was seen in only a small fraction of cells staining positive for vimentin and αSMA. However, PDGFRα showed significant co-localization with adipocyte markers, including PPAR-γ, adiponectin, and perilipin A. Oil red O staining confirmed that the mature adipocytes appearing in rotator cuff muscles after injury are also PDGFRα +. Conclusion: these data demonstrated that the Tie2 + muscle mesenchymal progenitors are the major source of fibroblasts while PDGFRα + FAPs are the major source of adipocytes in rotator cuff muscle fatty infiltration. Basic Science Study.

Histologic Differences in Human Rotator Cuff Muscle Based on Tear Characteristics

“…Rowshan et al 39 noted, in a rabbit animal study, that tendon tenotomy and nerve transection lead to similar patterns of fatty accumulation. Supporting this work, several studies using mice have found similar evidence to link rotator cuff tears and neuropathic muscle atrophy 40-44 . As was the case in our study, Rowshan et al noted that muscles in their group with a partial rotator cuff tear did not display evidence of increased fatty accumulation 39 .…”

Identify differential gene expressions in fatty infiltration process in rotator cuff

“…Another massive rotator cuff tear model caused by a full-thickness tenectomy of the right supraspinatus and infraspinatus in rats showed that the muscle fiber force is decreased and expressions of fibrosis and lipid accumulation related genes were increased [21]. A further study performed by Liu et al demonstrated that the main cellular sources involved in fatty infiltration were Tie2 + progenitor cells and fibro/adipogenic progenitor cells [22]. These three studies were consistent with the clinical reports and researches.…”

Challenges and perspectives of tendon-derived cell therapy for tendinopathy: from bench to bedside

“…The degree of fatty infiltration can be assessed by computerised tomography (CT) scan, magnetic resonance imaging (MRI) and ultrasound [120]. The origin of fatty infiltration is largely thought to be through adipocyte differentiation of the PDGFRα( +) fibro/adipogenic progenitor cells (FAPs) residing in muscle [121]. However, fatty infiltration seems to progress from MTJ into muscle after tendon injury, raising the possibility that the signals or cells from tendon may contribute to fatty infiltration in MTJ and/or muscles [122] (Fig.…”