Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses
Toll-like receptors on human mesenchymal stem cells drive their migration and immunomodulating responses
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DOI：
10.1634/stemcells.2007-0563
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发表时间：
2008-01-01
期刊：
影响因子：
5.2
通讯作者：
Scandurro, Aline B.
中科院分区：
文献类型：
--
作者：
Tomchuck, Suzanne L.;Zwezdaryk, Kevin J.;Scandurro, Aline B.
成人骨髓来源的间充质干细胞 (hMSC) 正在研究作为治疗递送剂，帮助修复受损组织。为了实现该策略所需的临床结果，需要更好地了解驱动 hMSC 招募、迁移和植入目标组织的机制。众所周知，hMSC 被募集到应激或炎症部位以实现其修复功能。人们认识到，Toll 样受体 (TLR) 介导其他骨髓来源细胞的应激反应。本研究探讨了 TLR 在介导 hMSC 应激反应中的作用。因此，hMSC 中 TLR 的存在最初是通过逆转录聚合酶链反应测定确定的。流式细胞术和荧光免疫细胞化学分析证实了这些发现。 TLR 激动剂刺激 hMSC 导致下游信号通路激活，包括核因子 kappa B、AKT 和 MAPK。因此，根据 cDNA 阵列、免疫测定和细胞因子抗体阵列分析确定，这些途径的激活触发了细胞因子、趋化因子和相关 TLR 基因产物的诱导和分泌。有趣的是，所测量的受影响基因、细胞因子和趋化因子的独特模式将这些受体确定为临床上观察到的 hMSC 免疫调节的关键参与者。最后，如 Transwell 迁移测定所示，TLR 配体暴露促进了 hMSC 迁移。相反，通过中和 TLR 抗体破坏 TLR 会损害 hMSC 迁移。这项研究定义了一种新型 TLR 驱动的 hMSC 应激和免疫调节反应，这对于设计基于干细胞的疗法至关重要。
Adult human bone marrow-derived mesenchymal stem cells (hMSCs) are under study as therapeutic delivery agents that assist in the repair of damaged tissues. To achieve the desired clinical outcomes for this strategy requires a better understanding of the mechanisms that drive the recruitment, migration, and engraftment of hMSCs to the targeted tissues. It is known that hMSCs are recruited to sites of stress or inflammation to fulfill their repair function. It is recognized that toll-like receptors (TLRs) mediate stress responses of other bone marrow-derived cells. This study explored the role of TLRs in mediating stress responses of hMSCs. Accordingly, the presence of TLRs in hMSCs was initially established by reverse transcription-polymerase chain reaction assays. Flow cytometry and fluorescence immunocytochemical analyses confirmed these findings. The stimulation of hMSCs with TLR agonists led to the activation of downstream signaling pathways, including nuclear factor kappa B, AKT, and MAPK. Consequently, activation of these pathways triggered the induction and secretion of cytokines, chemokines, and related TLR gene products as established from cDNA array, immunoassay, and cytokine antibody array analyses. Interestingly, the unique patterns of affected genes, cytokines, and chemokines measured identify these receptors as critical players in the clinically established immunomodulation observed for hMSCs. Lastly, hMSC migration was promoted by TLR ligand exposure as demonstrated by transwell migration assays. Conversely, disruption of TLRs by neutralizing TLR antibodies compromised hMSC migration. This study defines a novel TLR-driven stress and immune modulating response for hMSCs that is critical to consider in the design of stem cell-based therapies.