Tendon stem/progenitor cells regulate inflammation in tendon healing via JNK and STAT3 signaling

Tendon stem/progenitor cells (TSCs) have been found in different anatomic locations and showed a promising regenerative potential. We identified a role of TSCs in the regulation of inflammation during healing of acute tendon injuries. Delivery of connective tissue growth factor (CTGF) into full-transected rat patellar tendons significantly increased the number of CD146(+) TSCs, leading to enhanced healing. In parallel, CTGF delivery significantly reduced the number of iNOS(+) M1 macrophages and increased the expression of anti-inflammatory IL-10 at 2 d after surgery, with over 85% CD146(+) TSCs expressing IL-10. By 1 wk, the elevated IL-10 expression remained, and IL-6 expression was significantly attenuated in CTGF-delivered tendon healing. Matrix metalloproteinase (MMP)-3 expression in CTGF-delivered tendon was organized along with the reorienting collagen fibers by 1 wk after surgery, in comparison with the control group showing the abundant MMP-3 expression localized at healing junction. Tissue inhibitor of metalloprotease (TIMP)-3 was expressed in CD146(+) TSCs at 1 wk with CTGF, in contrast to control with no TIMP-3 expression. In vitro, IL-10 expression was detected only when tendon cells were stimulated with IL-1 beta, and CTGF and significantly higher in CD146(+) TSCs than CD146(-) tendon cells. Similarly, TIMP-3 expression was detected only when treated with CTGF or CTGF and IL-1b that is significantly higher in CD146(+) TSCs compared to CD146(-) tendon cells. Signaling study with specific inhibitors and Western blot analysis demonstrated that CTGF-induced expression of IL-10 and TIMP-3 in CD146(+) TSCs are regulated by JNK/signal transducer and activator of transcription 3 signaling. Taken together, these findings suggest anti-inflammatory roles of CTGF-stimulated TSCs that are likely associated with improved tendon healing.