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

ABSTRACT 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‐1β, 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‐1β 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.—Tarafder, S., Chen, E., Jun, Y., Kao, K., Sim, K. H., Back, J., Lee, F. Y., Lee, C. H. Tendon stem/progenitor cells regulate inflammation in tendon healing via JNK and STAT3 signaling. FASEB J. 31, 3991–3998 (2017). www.fasebj.org—Tarafder, Solaiman, Chen, Esther, Jun, Yena, Kao, Kristy, Sim, Kun Hee, Back, Jungho, Lee, Francis Y., Lee, Chang H. Tendon stem/progenitor cells regulate inflammation in tendon healing via JNK and STAT3 signaling. FASEB J. 31, 3991–3998 (2017)