State Key Laboratory of Military Stomatology, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, China.
Xi'an Institute of Tissue Engineering and Regenerative Medicine, Xi'an, China.
FASEB J. 2018 Apr;32(4):1982-1992. doi: 10.1096/fj.201700885R. Epub 2018 Jan 5.
Bone marrow-derived mesenchymal stem cell (BMSC) cytotherapy has emerged as a promising treatment strategy for refractory immune diseases; however, the influence of the pathologic conditions of donors on the immunomodulatory properties of BMSCs is still poorly understand. Here, we found that BMSCs that were derived from donors with osteoporosis were ineffective as cytotherapy for patients with experimental colitis and graft- vs.-host disease (GVHD). In vivo and in vitro assays revealed that the capacity of osteoporotic BMSCs to induce T-cell apoptosis declined as a result of decreased Fas and FasL protein. Additional analysis revealed that let-7a, a microRNA induced by TNF-α in osteoporosis, inhibited the expression of the Fas/FasL system via post-transcriptional regulation. By knocking down let-7a expression, we successfully recovered the immunosuppressive capacity of osteoporotic BMSCs and improved their therapy for experimental colitis and GVHD. Taken together, our study demonstrates that the immunomodulatory properties of BMSCs are suppressed in osteoporosis and illustrates the molecular mechanism that underlies this suppression. These findings might have important implications for the development of targeted strategies to improve BMSC cytotherapy.-Liao, L., Yu, Y., Shao, B., Su, X., Wang, H., Kuang, H., Jing, H., Shuai, Y., Yang, D., Jin, Y. Redundant let-7a suppresses the immunomodulatory properties of BMSCs by inhibiting the Fas/FasL system in osteoporosis.
骨髓间充质干细胞（BMSC）细胞疗法已成为治疗难治性免疫疾病的一种有前途的治疗策略；然而，供体病理状况对 BMSC 免疫调节特性的影响仍知之甚少。在这里，我们发现，骨质疏松症供体来源的 BMSC 对实验性结肠炎和移植物抗宿主病（GVHD）患者的细胞治疗无效。体内和体外实验表明，骨质疏松症 BMSC 诱导 T 细胞凋亡的能力下降，原因是 Fas 和 FasL 蛋白减少。进一步的分析表明，let-7a 是 TNF-α在骨质疏松症中诱导的一种 microRNA，通过转录后调控抑制 Fas/FasL 系统的表达。通过敲低 let-7a 的表达，我们成功地恢复了骨质疏松症 BMSC 的免疫抑制能力，并改善了它们对实验性结肠炎和 GVHD 的治疗效果。综上所述，我们的研究表明，BMSC 的免疫调节特性在骨质疏松症中受到抑制，并阐明了这种抑制的潜在分子机制。这些发现可能对开发靶向策略改善 BMSC 细胞治疗具有重要意义。
