Tarafder Solaiman, Chen Esther, Jun Yena, Kao Kristy, Sim Kun Hee, Back Jungho, Lee Francis Y, Lee Chang H
Regenerative Engineering Laboratory, Columbia University Irving Medical Center, New York, New York, USA.
Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, Connecticut, USA.
FASEB J. 2017 Sep;31(9):3991-3998. doi: 10.1096/fj.201700071R. Epub 2017 May 22.
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. , 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 JNK and STAT3 signaling.
肌腱干/祖细胞（TSCs）已在不同解剖位置被发现，并显示出有前景的再生潜力。我们确定了TSCs在急性肌腱损伤愈合过程中炎症调节中的作用。将结缔组织生长因子（CTGF）注入完全横断的大鼠髌腱中可显著增加CD146 TSCs的数量，从而促进愈合。同时，术后2天时，CTGF的注入显著减少了诱导型一氧化氮合酶（iNOS）M1巨噬细胞的数量，并增加了抗炎性白细胞介素-10（IL-10）的表达，超过85%的CD146 TSCs表达IL-10。到1周时，IL-10的高表达持续存在，且在CTGF注入促进的肌腱愈合中，白细胞介素-6（IL-6）的表达显著减弱。与对照组相比，对照组中基质金属蛋白酶-3（MMP-3）的表达大量定位于愈合连接处，而术后1周时，CTGF注入促进的肌腱中MMP-3的表达与重新定向的胶原纤维排列在一起。金属蛋白酶组织抑制剂-3（TIMP-3）在术后1周时经CTGF处理的情况下在CD146 TSCs中表达，而对照组则无TIMP-3表达。此外，仅当肌腱细胞受到IL-1β刺激时才检测到IL-10的表达，且CTGF处理时，CD146 TSCs中的IL-10表达明显高于CD146肌腱细胞。同样，仅在经CTGF或CTGF与IL-1β处理时才检测到TIMP-3的表达，且与CD146肌腱细胞相比，CD146 TSCs中的TIMP-3表达明显更高。使用特异性抑制剂的信号研究和蛋白质免疫印迹分析表明，CTGF诱导的CD146 TSCs中IL-10和TIMP-3的表达受JNK/信号转导子和转录激活子3信号通路调控。综上所述，这些发现提示CTGF刺激的TSCs具有抗炎作用，这可能与肌腱愈合改善相关。——塔拉夫德，S.，陈，E.，朱恩，Y.，考，K.，西姆，K.H.，巴克，J.，李，F.Y.，李，C.H. 肌腱干/祖细胞通过JNK和STAT3信号通路调节肌腱愈合中的炎症
