Daniel Lindahl

Introduction: Achilles tendon ruptures are extremely prevalent in both athletes and the general populace, accounting for 20% of all large tendon ruptures.¹ Both surgical and non-surgical treatment are aimed at approximating tendon edges to promote healing, however re-rupture rates remain high due to unresolved inflammation.^1,2 Macrophages play a critical role in both up-regulating and resolving inflammation through the M1/M2 pathway. Targeting this pathway reduces inflammation as a means to promote further healing.^1,2 Recent studies demonstrated the therapeutic potency of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) in achilles tendon healing by modulating the M1/M2 macrophage ratio.^3,4 Methods and Results: The therapeutic potency of MSCs in wound healing was first investigated. Experimental groups that contained MSCs showed increased wound closure, while macrophage knockout groups (control and MSC) showed delayed wound repair.⁵ This result confirmed the key role of macrophages in MSC-mediated wound healing.⁵ The ability of MSC-derived EVs (MSC-EVs) to modulate the inflammatory M1 phenotype and anti-inflammatory M2 phenotype was then investigated. Lipopolysaccharide (LPS) was used to stimulate macrophage-produced inflammatory cytokines as a means to quantify M1 vs M2 polarization (IL-1, IFN, IL-10, and IL-4).^6,7,8 Results showed that MSC-EVs were able to promote the M2 phenotype while inhibiting the M1 phenotype, leading to increased granulation tissue and improved achilles tendon strength in rat models of achilles tendon injury.^4,6 Mechanistically, MSC-EVs upregulated the PTEN/AKT pathway, which drives IL-10 production while inhibiting inflammatory cytokines IL-1 and TNF, thereby modulating the M1/M2 macrophage ratio.⁹ Importantly, miR-146a in MSC-EVs was identified as a key molecular link responsible for the EV-mediated PTEN upregulation, as EVs lacking miR-146a showed significant reduction in M1/M2 modulation.^10,11 Conclusion: MSC-EVs were able to modulate the M1/M2 macrophage pathway which resulted in increased granulation tissue and improved achilles tendon strength in pre-clinical models. Their use may be considered clinically as a viable addition to both surgical  and non-surgical treatment pending further research.

1. Park, S. H., et al. (2020). “Treatment of Acute Achilles Tendon Rupture.” Clin Orthop Surg 12(1): 1-8.
2. Maempel, J. F., et al. (2022). “The epidemiology of Achilles tendon re-rupture and associated risk factors: male gender, younger age and traditional immobilising rehabilitation are risk factors.” Knee Surg Sports Traumatol Arthrosc.
3. Cottom, J. M. and B. S. Plemmons (2018). “Bone Marrow Aspirate Concentrate and Its Uses in the Foot and Ankle.” Clin Podiatr Med Surg 35(1): 19-26.
4. Chamberlain, C. S., et al. (2019). “Extracellular Vesicle-Educated Macrophages Promote Early Achilles Tendon Healing.” Stem Cells 37(5): 652-662.
5. He, X., et al. (2019). “MSC-Derived Exosome Promotes M2 Polarization and Enhances Cutaneous Wound Healing.” Stem Cells Int 2019: 7132708.
6. Aktas, E., et al. (2017). “Immune modulation with primed mesenchymal stem cells delivered via biodegradable scaffold to repair an Achilles tendon segmental defect.” J Orthop Res 35(2): 269-280.
7. Genard, G., et al. (2017). “Reprogramming of Tumor-Associated Macrophages with Anticancer Therapies: Radiotherapy versus Chemo- and Immunotherapies.” Front Immunol 8: 828.
8. Alcaraz, M. J., et al. (2019). “Extracellular Vesicles from Mesenchymal Stem Cells as Novel Treatments for Musculoskeletal Diseases.” Cells 9(1).
9. Liu, W., et al. (2020). “Melatonin-stimulated MSC-derived exosomes improve diabetic wound healing through regulating macrophage M1 and M2 polarization by targeting the PTEN/AKT pathway.” Stem Cell Res Ther 11(1): 259.
10. Shen, H., et al. (2020). “Stem cell-derived extracellular vesicles attenuate the early inflammatory response after tendon injury and repair.” J Orthop Res 38(1): 117-127.
11. Song, Y., et al. (2017). “Exosomal miR-146a Contributes to the Enhanced Therapeutic Efficacy of Interleukin-1β-Primed Mesenchymal Stem Cells Against Sepsis.” Stem Cells 35(5): 1208-1221