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

Abstract

SummaryBackground: 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.

Fatty infiltration of the minor salivary glands is a selective feature of aging but not Sjögren’s syndrome

“…Fatty infiltration and fatty replacement are terms that describe processes by which tissue, generally exocrine tissue, is replaced in whole or in part by adipocytes [33, 34, 35]. Fatty infiltration of tissue is a normal part of the aging process, though pathological and accelerated forms can occur after tissue injury [36, 37]. Thymic involution, for example, is a systematic replacement of thymic tissue with adipocytes which occurs as an organism ages [38].…”

“…Fatty replacement due to soft tissue injury has been described in soft tissues (especially that of the rotator cuff [37]), traumatic bone injury [39] and in pancreatic injury due to primary duct stenosis or calcification [33, 34, 35]. In well-characterized rodent models of pancreatic duct ligation, the pancreatic tissue undergoes a series of predictable alterations.…”

The role of mechanobiology in progression of rotator cuff muscle atrophy and degeneration

“…, Pro‐Myogenic FAPs, Adipogenic FAPs ), dysfunction of FAP's could be implicated in all three detrimental changes in torn RC (muscle loss, fibrosis/stiffening, and fat accumulation). Indeed, the conditions under which FAPs take on an adipogenic fate exist in the inflammatory environment of the torn human RC, and a small animal model has shown potential for adipogenic differentiation of FAPs in the context of RC tear …”

Animal models for rotator cuff repair

“…used mouse RC muscles harvested at 2 and 6 weeks after unilateral massive RC tear surgeries to investigate the cellular origin of fatty infiltration. They demonstrated that the Tie2 + muscle mesenchymal progenitors are the major source of fibroblasts, while platelet‐derived growth factor (PDGF)‐α + fibro/adipogenic progenitor cells are the major source of adipocytes in RC muscle fatty infiltration …”