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 µg in 10 µL). 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.