Skeletal Stem Cell-Derived Exosomes Promote Meniscal Tear Healing and Ameliorate Secondary Osteoarthritis

Abstract

Background: The self-repair ability after meniscal tears is poor, leading to the development of posttraumatic osteoarthritis. Promoting the repair of meniscal injuries remains a great challenge, especially in the avascular region.

Hypothesis: Local delivery of skeletal stem cell (SSC)-derived exosomes (SSC-Exos) would promote meniscal healing and prevent secondary osteoarthritis progression.

Study design: Controlled laboratory study.

Methods: SSCs were isolated from bone marrow and exosomes were extracted via ultracentrifugation. The cell migration capabilities after incubation with exosomes were validated through in vitro cell culture. Full-thickness longitudinal medial meniscal tears were performed in the avascular region of 40 male Sprague-Dawley rats and 20 male New Zealand White rabbits, which were randomly divided into 2 groups: group treated with phosphate-buffered saline (G_CON) and group treated with exosomes (G_Exosome). The effects of these treatments on meniscal healing and secondary osteoarthritis were evaluated by gross inspection, biomechanical testing, and histological assessment. RNA sequencing of in vitro cell cultures was performed to explore the underlying mechanisms.

Results: Exosomes were successfully extracted and identified. These exosomes significantly promoted cell migration capabilities in vitro (P < .01). The G_Exosome exhibited greater cell proliferation and tissue regeneration with type 2 collagen secretion, and a significantly higher meniscal repair score than that of the G_CON at 8 weeks postoperatively (P < .05). In contrast to the degenerative changes in both the meniscus and articular cartilage of the G_CON, meniscal tissue in the G_Exosome exhibited restoration of normal morphology with a smooth and glossy white surface and better mechanical strength at 8 weeks after meniscal repair. Both degeneration scores and synovitis scores were significantly higher in the G_CON than in the G_Exosome (P < .05). Compared with the G_CON, the expression of key genes related to cell migration, such as the chemokine family, was enhanced by exosome injection, leading to an upregulation of extracellular matrix expression while downregulating the expression of inflammation-related genes such as CD68 and the matrix metalloproteinase family.

Conclusion: The administration of SSC-Exos effectively promoted meniscal healing in the avascular region and ameliorated secondary osteoarthritis. The effect might be attributed to inflammation modulation, promotion of cell migration, and secretion of extracellular matrix components.

Clinical relevance: Injection of SSC-Exos represents a promising therapeutic option for promoting meniscal healing in the avascular region.

Keywords: exosomes; knee joint; meniscal healing; meniscal injury; skeletal stem cells.