Mesenchymal Stem Cell–Derived Exosome Efficacy and Safety in Musculoskeletal Tissues: State of the Art and Future Directions Publisher



Eshraghi N^{1, 2} ; Javidan A³ ; Alsaeidi NN⁴ ; Makuku R¹ ; Mortezaei A⁵ ; Mirghaderi P¹
Source: Regenerative Engineering and Translational Medicine Published:2025

Abstract

Background: Mesenchymal Stem Cell Extracellular Vesicles (MSC-EVs), particularly exosomes, have been researched as promising therapeutic agents. This narrative review focuses on the potential roles of these extracellular vesicles in orthopedic surgery, focusing on their contributions to musculoskeletal tissue regeneration and inflammatory regulation spanning bone, cartilage, tendons, and ligaments. EVs augment bone defect healing by augmenting osteoblastic proliferation and facilitating stromal progenitor cell infiltration. This promotes reossification, evident in the elevation of bone volume, expansion of bone growth regions, and enhanced histological bone healing. Furthermore, these vesicles foster osteogenesis and angiogenesis, potentially mediated through interactions with various cellular entities, notably bone marrow-derived MSCs (BM-MSCs) and endothelial cells. Within the realm of articular cartilage repair, MSC-EVs have demonstrated immunomodulatory roles by curbing damaging T-cell-mediated autoimmune diseases, promoting tissue regeneration, and inhibiting pro-inflammatory mediators. Results: Novel advances spotlight the conjunction of bioactive molecules with engineered exosomes to promote chondrogenesis, offering advancements in joint function optimization. Furthermore, this technology is proving to be groundbreaking in tendons and ligaments, where inherent healing capacities are limited in the fibrous tissues. The MSC-EV composite has showcased an ability to bolster revascularization, enhance intracellular signaling and protein delivery, and reduce unfavorable scar tissue formation, which potentially decreases the possibility of subsequent tissue rupture. Despite these promising experimental breakthroughs, challenges persist as the therapeutic utility of MSC-EVs hinges on their tissue-specific origin. This implies a necessity for pathology-tailored procurement and engineering to harness the potential of endogenous repair mechanisms within orthopedic applications. Conclusion: As this therapy emerges as a promising alternative to managing common orthopedic pathologies, especially in inflammatory settings, larger clinical trials are imperative. These trials will solidify the benefits, elucidate potential limitations and their applicable feasibility, and set a roadmap for the hopeful future of MSC-EVs in aiding the endogenous repair pathways into the standard of care, revolutionizing the treatment paradigms for orthopedic care. Lay summary: In the United States, skeletal disorders are a prevalent contributor to disability. The existing therapeutic interventions demonstrate relative effectiveness in mitigating morbidity and alleviating pain; nonetheless, a substantial proportion of individuals fail to achieve recovery. Conversely, the majority of current treatments do not have significant long-term effects and have limitations. The widespread availability and cost-effectiveness of mesenchymal stromal/stem cells (MSC) are key factors in their significant utilization. Multiple experimental studies have provided evidence that MSC-Exosome exhibits significant inhibitory effects on inflammatory and autoimmune processes, as well as the ability to facilitate tissue repair in injured tissues. This innovative treatment has the potential to revolutionize the field and serve as the primary treatment option for most individuals suffering from musculoskeletal disorders. © The Author(s), under exclusive licence to The Regenerative Engineering Society 2025.