Redundant let-7a suppresses the immunomodulatory properties of BMSCs by inhibiting the Fas/FasL system in osteoporosis
Redundant let-7a suppresses the immunomodulatory properties of BMSCs by inhibiting the Fas/FasL system in osteoporosis
复制标题
骨质疏松症中冗余let-7a通过抑制Fas/FasL系统来抑制BMSC的免疫调节特性
DOI：
10.1096/fj.201700885r
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发表时间：
2018-04-01
期刊：
影响因子：
4.8
通讯作者：
Jin, Yan
中科院分区：
文献类型：
--
作者：
Liao, Li;Yu, Yang;Jin, Yan
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景的治疗策略；然而，供体病理条件对骨髓间充质干细胞免疫调节特性的影响尚不清楚。在这里，我们发现来自骨质疏松症供体的骨髓间充质干细胞对实验性结肠炎和移植物vs患者的细胞治疗无效。-宿主病（GVHD）。体内和体外实验表明，由于Fas和FasL蛋白的减少，骨质疏松性骨髓间充质干细胞诱导t细胞凋亡的能力下降。进一步的分析显示，在骨质疏松症中由tnf - α诱导的小rna let-7a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，我们成功恢复了骨质疏松性骨髓间充质干细胞的免疫抑制能力，并改善了它们对实验性结肠炎和GVHD的治疗。综上所述，我们的研究表明骨髓间充质干细胞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分子机制。这些发现可能对开发靶向策略以改善BMSC细胞治疗具有重要意义。
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-alpha 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.