Comparative Effects of Exosomes and Ectosomes Isolated From Adipose-Derived Mesenchymal Stem Cells on Achilles Tendinopathy in a Rat Model

Abstract

Background: Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have gained momentum as a treatment for tendinopathy. Multiple studies have demonstrated significant differences in cargo composition between the 2 subtypes of MSC-EVs (ie, exosomes and ectosomes), which may result in different therapeutic effects. However, the effects of the 2 EV subtypes on tendinopathy have not yet been compared. Purpose: To compare the effects of adipose stem cell–derived exosomes (ASC-Exos) and ectosomes (ASC-Ectos) on Achilles tendinopathy. Study Design: Controlled laboratory study. Methods: Rats were administered collagenase injections to generate a model of Achilles tendinopathy. A week later, 36 rats were randomly assigned to 3 groups. In each group, Achilles tendons were injected with equal volumes of ASC-Exos, ASC-Ectos, or saline (12 legs/group). The healing outcomes were evaluated by magnetic resonance imaging, histology, immunohistochemistry, transmission electron microscopy, and biomechanical testing at 3 and 5 weeks after collagenase injection. Results: At 3 and 5 weeks, the ASC-Exo group had better histological scores ( P = .0036 and P = .0276, respectively), a lower fibril density ( P < .0001 and P = .0310, respectively), and a larger collagen diameter ( P = .0052 and P < .0001, respectively) than the ASC-Ecto group. At 5 weeks, the expression of collagen type 1 and CD206 in the ASC-Exo group was significantly higher than that in the ASC-Ecto group ( P = .0025 and P = .0010, respectively). Regarding biomechanical testing, the ASC-Exo group showed higher failure load ( P = .0005), tensile stress ( P < .0001), and elastic modulus ( P < .0001) than the ASC-Ecto group. Conclusion: ASC-Exos had more beneficial effects on tendon repair than ASC-Ectos in a rat model of Achilles tendinopathy. Clinical Relevance: Administration of ASC-EVs may have the potential to treat Achilles tendinopathy, and delivery of ASC-Exos could provide additional benefits. It is necessary to compare the healing responses caused by different EV subtypes to further understand their effects on tendinopathy and to aid clinical decision making.

Global trends in research of achilles tendon injury/rupture: A bibliometric analysis, 2000–2021

“…In 2019, Chamberlain et al utilized exosome-educated macrophage–treated ATI exhibiting (a) improved mechanical properties, (b) reduced inflammation, and (c) earlier angiogenesis ( 32 ). Meanwhile, extracellular vesicles derived from mesenchymal stem cells have gained much momentum in the treatment of tendinopathies ( 33 ). Mesenchymal stem cells are a hot topic in the field of tendon regeneration engineering ( 34 ).…”

Comparison of the ability of exosomes and ectosomes derived from adipose-derived stromal cells to promote cartilage regeneration in a rat osteochondral defect model

“…The Animal Ethics Committee of the 2nd Affiliated Hospital, School of Medicine, Zhejiang University approved the animal research ethics. Isolation and culture of primary adipose-derived MSCs (ASCs) and chondrocytes from Sprague–Dawley rats were performed as we have described previously [ 21 , 22 ]. Briefly, minced adipose tissue was digested with 0.1% collagenase type I and cartilage particles were digested with 0.2% collagenase II at 37 °C for 4 h. Next, collected cells were seeded into 25-mm 2 culture flasks with corresponding mediums containing 10% fetal bovine serum (FBS).…”

“…Adipose-derived stem cells (ASCs) possess numerous desirable advantages, such as a less invasive collection process, high cellular yield, and great expansion capability [ 20 ]. In our prior study, we isolated exosomes and ectosomes from ASCs and analyzed their different micro-RNA expression profiles, though they partially overlap in size [ 21 ]. As we demonstrate, ASC-Exos have a stronger ability to inhibit inflammation than ASC-Ectos under the pathological condition of tendinopathy.…”

Exosomes: The New Kid on the Block in Orthobiologics

“…Similarly, a rat model of Achilles tendonopathy found that MSC-derived EVs resulted in improved histological scores with improvements in collagen fibril diameter and superior biomechanical properties. 19 MSC-derived EVs have also been shown to improve ligament healing in a rat medial collateral ligament injury model, with increased expression of type 1 and type 3 collagen, improved collagen organization, and reduction in scar size. 3…”