Yang Zhigang, Dong Ping, Fu Xin, Li Qiuchen, Ma Shize, Wu Dongying, Kang Ning, Liu Xia, Yan Li, Xiao Ran
Research Center of Plastic Surgery Hospital, Chinese Academy of Medical Sciences & Peking Union of Medical College, Beijing, People's Republic of China.
307-Ivy Translational Medicine Center, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, People's Republic of China.
Stem Cells. 2015 Sep;33(9):2798-810. doi: 10.1002/stem.2063. Epub 2015 Jun 23.
The advent of mesenchymal stem cell (MSC)-based therapies has been an exciting innovation for the treatment of degenerative and inflammatory diseases. However, the surface markers that accurately reflect the self-renewal and differentiation potential of MSCs and their sensitivity to environmental cues remain poorly defined. Here, we studied the role of CD49f in bone marrow MSCs (BMSCs) and the mechanism by which it regulates the behavior of BMSCs under inflammatory conditions. We found that CD49f is preferentially expressed in fetal cells rather than adult cells, CD49f-positive BMSCs possess higher CFU-F formation ability and differentiation potential than CD49f negative cells, and the CD49f expression of BMSCs gradually decreases during in vitro passaging. CD49f knockdown dramatically decreased the differentiation of BMSCs and isoform A was demonstrated to be the main functional form that enhanced the differentiation ability of BMSCs. The influences of inflammatory cytokines on BMSCs revealed that TNF-α downregulated CD49f in BMSCs with impaired differentiation, decreased adhesion to laminins, and increased migration. Moreover, tissue transglutaminase was found to work together with CD49f to regulate the behavior of BMSCs. Finally, we showed that mTOR signaling rather than NF-κB activation mediated CD49f downregulation induced by TNF-α and maintained CD49f homeostasis in BMSCs. Our findings suggest that CD49f is a stemness marker of BMSCs and is tightly correlated with the behavioral changes of BMSCs under inflammatory conditions. These data demonstrate a novel role for CD49f in sensing inflammation through mTOR pathway to further modulate the behavior of MSCs to fulfill the requirements of the body.
基于间充质干细胞（MSC）的疗法的出现，是治疗退行性和炎症性疾病的一项令人兴奋的创新。然而，能够准确反映MSC自我更新和分化潜力及其对环境信号敏感性的表面标志物仍未明确界定。在此，我们研究了CD49f在骨髓间充质干细胞（BMSC）中的作用及其在炎症条件下调节BMSC行为的机制。我们发现CD49f在胎儿细胞中优先表达而非成人细胞，CD49f阳性的BMSC比CD49f阴性细胞具有更高的集落形成单位 - 成纤维细胞（CFU - F）形成能力和分化潜力，并且BMSC的CD49f表达在体外传代过程中逐渐降低。敲低CD49f显著降低了BMSC的分化，并且亚型A被证明是增强BMSC分化能力的主要功能形式。炎症细胞因子对BMSC的影响表明，肿瘤坏死因子 - α（TNF - α）下调分化受损的BMSC中的CD49f，降低对层粘连蛋白的粘附，并增加迁移。此外，发现组织转谷氨酰胺酶与CD49f共同作用来调节BMSC的行为。最后，我们表明哺乳动物雷帕霉素靶蛋白（mTOR）信号传导而非核因子κB（NF - κB）激活介导了TNF - α诱导的CD49f下调并维持BMSC中的CD49f稳态。我们的研究结果表明，CD49f是BMSC的干性标志物，并且与炎症条件下BMSC的行为变化密切相关。这些数据证明了CD49f在通过mTOR途径感知炎症以进一步调节MSC行为以满足身体需求方面的新作用。
