Cell senescence abrogates the therapeutic potential of human mesenchymal stem cells in the lethal endotoxemia model.
Cell senescence abrogates the therapeutic potential of human mesenchymal stem cells in the lethal endotoxemia model.
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DOI：
10.1002/stem.1654
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发表时间：
2014-07
期刊：
影响因子：
5.2
通讯作者：
Gonzalez, Manuel A.
中科院分区：
文献类型：
--
作者：
Carlos Sepulveda, Juan;Tome, Maria;Eugenia Fernandez, Maria;Delgado, Mario;Campisi, Judith;Bernad, Antonio;Gonzalez, Manuel A.
骨髓间充质干细胞（Mesenchymal stem cells，MSCs）具有独特的旁分泌和免疫抑制特性，可作为细胞治疗的候选细胞。在这里，我们讨论了细胞衰老如何影响人骨髓间充质干细胞（hMSC）的治疗潜力。用γ射线照射诱导骨髓来源的hMSC培养物衰老。在体外和体内测试了对照和衰老细胞的免疫调节活性，并对衰老诱导的表型变化进行了广泛的分子表征。我们还比较了衰老的hMSCs与正在进行的移植物抗宿主病（GVHD）临床研究中使用的hMSCs的基因表达谱。我们的研究结果表明，衰老诱导广泛的表型变化的hMSCs和废除其保护活性的LPS诱导的致死性内毒素血症的小鼠模型。尽管衰老的hMSC保留了体外调节巨噬细胞炎症反应的能力，并且部分保留了其显著抑制淋巴细胞增殖的能力，但它们响应于促炎信号的迁移能力严重受损，这与AP-1途径的抑制有关。此外，表达分析鉴定了PLEC、C8 orf 48、TRPC 4和ZNF 14作为衰老hMSC中差异调节的基因，其在GVHD试验中未能产生治疗效果的那些hMSC中受到类似调节。所有观察到的表型改变在复制衰老的hMSCs中得到证实。总之，本研究突出了衰老hMSCs的免疫调节表型的重要变化，并提供了候选基因签名，这可能有助于评估hMSCs在未来临床研究中的治疗潜力。
Mesenchymal stem cells (MSCs) possess unique paracrine and immunosuppressive properties, which make them useful candidates for cellular therapy. Here, we address how cellular senescence influences the therapeutic potential of human MSCs (hMSCs). Senescence was induced in bone marrow-derived hMSC cultures with gamma irradiation. Control and senescent cells were tested for their immunoregulatory activity in vitro and in vivo, and an extensive molecular characterization of the phenotypic changes induced by senescence was performed. We also compared the gene expression profiles of senescent hMSCs with a collection of hMSCs used in an ongoing clinical study of Graft Versus Host disease (GVHD). Our results show that senescence induces extensive phenotypic changes in hMSCs and abrogates their protective activity in a murine model of LPS-induced lethal endotoxemia. Although senescent hMSCs retain an ability to regulate the inflammatory response on macrophages in vitro, and, in part retain their capacity to significantly inhibit lymphocyte proliferation, they have a severely impaired migratory capacity in response to proinflammatory signals, which is associated with an inhibition of the AP-1 pathway. Additionally, expression analysis identified PLEC, C8orf48, TRPC4, and ZNF14, as differentially regulated genes in senescent hMSCs that were similarly regulated in those hMSCs which failed to produce a therapeutic effect in a GVHD trial. All the observed phenotypic alterations were confirmed in replicative-senescent hMSCs. In conclusion, this study highlights important changes in the immunomodulatory phenotype of senescent hMSCs and provides candidate gene signatures which may be useful to evaluate the therapeutic potential of hMSCs used in future clinical studies.
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影响因子：
4.6
作者：
Edwards, MG;Sarkar, D;Prolla, TA
通讯作者：
Prolla, TA
影响因子：
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作者：
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通讯作者：
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通讯作者：
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影响因子：
24.5
作者：
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通讯作者：
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