Anti-inflammatory and Tendon-Protective Effects of Adipose Stem Cell-Derived Exosomes with Concomitant Use of Glucocorticoids

Glucocorticoid (GC) injections are commonly used in clinical practice to relieve pain and improve function in patients with multiple shoulder disabilities but cause detrimental effects on rotator cuff tendons. Adipose stem cell-derived exosomes (ASC-Exos) reportedly recover impaired tendon matrix metabolism by maintaining tissue homeostasis. However, it is unclear whether additional treatment with ASC-Exos overrides the detrimental effects of GCs without interfering with their anti-inflammatory effects. Thus, we aimed to investigate the anti-inflammatory effect of ASC-Exos with GCs and protective effect of ASC-Exos against GC-induced detriments. The present study comprised in vitro and in vivo studies. In vitro inflammatory analysis revealed that ASC-Exos exerted a synergic anti-inflammatory effect with GCs by significantly decreasing secretion of proinflammatory cytokines by RAW cells and increasing secretion of anti-inflammatory cytokines. In vitro cytoprotective analysis showed that ASC-Exos overrode GC-induced detrimental effects on tenocytes by significantly improving GC-suppressed cellular proliferation, migration, and transcription of tenocytic matrix molecules and degradative enzyme inhibitors and significantly decreasing GC-induced cell senescence, apoptosis, and transcription of ROS and tenocytic degradative enzymes. In vivo studies revealed that additional ASC-Exo injection restored impairments in histological and biomechanical properties owing to GC administration. Collectively, these results suggest that ASC-Exos exert a stronger anti-inflammatory effect in combination with GCs, overriding their detrimental effects on rotator cuff tendons.