Insulin-Like Growth Factor 1 in Exosomes Derived from Adipose-Derived Stem Cells Promotes Tendon-Bone Healing in Rotator Cuff Injuries.

Abstract

BACKGROUND: Rotator cuff injuries are common musculoskeletal disorders and are frequently complicated by impaired tendon-bone healing and high re-tear rates after surgical repair. Exosomes derived from adipose-derived stem cells (ADSCs) have shown regenerative potential through paracrine mechanisms; however, the role of exosomal insulin-like growth factor 1 (IGF1) in tendon-bone healing remains unclear. METHODS: Exosomes were isolated from rat ADSCs with or without lentiviral knockdown of IGF1. A rat supraspinatus tendon tear and repair model was established, and 200 μg of exosomes was administered systemically post-surgery. Tendon-bone healing was evaluated at 8 weeks post-operation using histological, immunohistochemical, and micro-computed tomography analyses. Early molecular responses were assessed at 1-week post-surgery by Western blot and RT-qPCR. Angiogenic markers (vascular endothelial growth factor (VEGF), CD31, α-SMA), inflammatory cytokines (interleukin (IL)-1β, IL-18), pyroptosis-related proteins (gasdermin D N-terminal fragment (GSDMD-N)), and NLRP3 inflammasome components were examined. RESULTS: ADSC-derived exosomes significantly enhanced bone mineral density, fibrocartilage formation, vascularization, and biomechanical strength at the tendon-bone interface. These effects were accompanied by reduced inflammatory cytokine expression, inhibition of pyroptosis, and suppression of NLRP3 inflammasome activation. In contrast, exosomes derived from IGF1-deficient ADSCs exhibited markedly reduced therapeutic efficacy, with attenuated angiogenic, anti-inflammatory, and anti-pyroptotic effects. CONCLUSIONS: Exosomal IGF1 plays a critical role in promoting angiogenesis, suppressing inflammation and pyroptosis, and improving structural and biomechanical outcomes during tendon-bone healing. IGF1-enriched ADSC-derived exosomes represent a promising therapeutic strategy for enhancing rotator cuff repair.