Extracellular vesicles from bone marrow-derived multipotent mesenchymal stromal cells regulate inflammation and enhance tendon healing

Background: Extracellular vesicles from bone marrow-derived multipotent mesenchymal stromal cells (BMSC-EVs) can play important roles in the repair of injured tissues. However, no reports have investigated the role and underlying mechanisms of BMSCs-EVs in the tendon repair process. We hypothesized that BMSC-EVs may play a role in modulating inflammation during tendon healing and improving tendon repair in a rat model of patellar tendon injury. Methods: First, we created window defects in the patellar tendons of Sprague-Dawley rats. Rats (n = 16) were then randomly assigned to three groups: BMSC-EVs group, Fibrin group, and control group. Rats in the BMSC-EVs group were treated with BMSC-EVs and fibrin glue (25 mu g in 10 mu L). Rats in the fibrin group were treated with fibrin only, and those in the control group received no treatment. Histopathology, immunohistochemistry, and gene expression analyses were performed at 2 and 4 weeks after surgery. Results: At 4 weeks, tendons treated with BMSC-EVs showed regularly aligned and compact collagen fibers as compared with the disrupted scar-like healing in rats in the fibrin and control groups. The expression of genes related to tendon matrix formation and tenogenic differentiation: collagen (COL)-1a1, scleraxis (SCX), and tenomodulin (TNMD) was significantly higher in the BMSC-EVs group than in the other two groups. With histopathology, we observed significantly higher numbers of CD146+ tendon stem cells and fewer numbers of apoptotic cells and C-C chemokine receptor type 7 (CCR7)-positive proinflammatory macrophages in the BMSC-EVs group. BMSC-EVs treatment also led to an increase in the expression of anti-inflammatory mediators (IL-10 and IL-4) at 2 weeks after surgery. Conclusions: Overall, our findings show that the local administration of BMSC-EVs promotes tendon healing by suppressing inflammation and apoptotic cell accumulation and increasing the proportion of tendon-resident stem/progenitor cells. These findings provide a basis for the potential clinical use of BMSC-EVs in tendon repair.