ISSLS PRIZE in Basic Science 2024: superiority of nucleus pulposus cell- versus mesenchymal stromal cell-derived extracellular vesicles in attenuating disc degeneration and alleviating pain
Luca Ambrosio, Jordy Schol, Clara Ruiz‐Fernández, Shota Tamagawa, Hazuki Soma, Veronica Tilotta, Giuseppina Di Giacomo, Claudia Cicione, Shunya Nakayama, K. Kamiya, Rocco Papalia, Masato Sato, Gianluca Vadalà, Masahiko Watanabe, Vincenzo Denaro, Daisuke Sakai
Abstract
Abstract Purpose To investigate the therapeutic potential of extracellular vesicles (EVs) derived from human nucleus pulposus cells (NPCs), with a specific emphasis on Tie2-enhanced NPCs, compared to EVs derived from human bone marrow-derived mesenchymal stromal cells (BM-MSCs) in a coccygeal intervertebral disc degeneration (IDD) rat model. Methods EVs were isolated from healthy human NPCs cultured under standard (NPC STD -EVs) and Tie2-enhancing (NPC Tie2+ -EVs) conditions. EVs were characterized, and their potential was assessed in vitro on degenerative NPCs in terms of cell proliferation and senescence, with or without 10 ng/mL interleukin (IL)-1β. Thereafter, 16 Sprague–Dawley rats underwent annular puncture of three contiguous coccygeal discs to develop IDD. Phosphate-buffered saline, NPC STD -EVs, NPC Tie2+ -EVs, or BM-MSC-derived EVs were injected into injured discs, and animals were followed for 12 weeks until sacrifice. Behavioral tests, radiographic disc height index (DHI) measurements, evaluation of pain biomarkers, and histological analyses were performed to assess the outcomes of injected EVs. Results NPC-derived EVs exhibited the typical exosomal morphology and were efficiently internalized by degenerative NPCs, enhancing cell proliferation, and reducing senescence. In vivo, a single injection of NPC-derived EVs preserved DHI, attenuated degenerative changes, and notably reduced mechanical hypersensitivity. MSC-derived EVs showed marginal improvements over sham controls across all measured outcomes. Conclusion Our results underscore the regenerative potential of young NPC-derived EVs, particularly NPC Tie2+ -EVs, surpassing MSC-derived counterparts. These findings raise questions about the validity of MSCs as both EV sources and cellular therapeutics against IDD. The study emphasizes the critical influence of cell type, source, and culture conditions in EV-based therapeutics.