Department of Internal Medicine, Korea University Anam Hospital, Seoul, Korea.
PLoS One. 2013 Aug 6;8(8):e72544. doi: 10.1371/journal.pone.0072544. Print 2013.
Previous studies have shown that induction of immune tolerance by mesenchymal stem cells (MSCs) is partially mediated via monocytes or dendritic cells (DCs). The purpose of this study was to determine the role of CD11c⁺ cells in MSC-induced effects on ischemia/reperfusion injury (IRI). IRI was induced in wildtype (WT) mice and CD11c⁺-depleted mice following pretreatment with or without MSCs. In the in-vitro experiments, the MSC-treated CD11c⁺ cells acquired regulatory phenotype with increased intracellular IL-10 production. Although splenocytes cocultured with MSCs showed reduced T cell proliferation and expansion of CD4⁺FoxP3⁺ regulatory T cells (Tregs), depletion of CD11c⁺ cells was associated with partial loss of MSCs effect on T cells. In in-vivo experiment, MSCs' renoprotective effect was also associated with induction of more immature CD11c⁺ cells and increased FoxP3 expression in I/R kidneys. However all these effects induced by the MSCs were partially abrogated when CD11c⁺ cells were depleted in the CD11c⁺-DTR transgenic mice. In addition, the observation that adoptive transfer of WT CD11c⁺ cells partially restored the beneficial effect of the MSCs, while transferring IL-10 deficient CD11c⁺ cells did not, strongly suggest the important contribution of IL-10 producing CD11c⁺ cells in attenuating kidney injury by MSCs. Our results suggest that the CD11c⁺ cell-Tregs play critical role in mediating renoprotective effect of MSCs.
先前的研究表明，间充质干细胞（MSCs）通过单核细胞或树突状细胞（DCs）部分诱导免疫耐受。本研究旨在确定 CD11c⁺细胞在 MSC 诱导的缺血/再灌注损伤（IRI）中的作用。在预处理后，用或不用 MSCs 诱导野生型（WT）小鼠和 CD11c⁺耗尽小鼠发生 IRI。在体外实验中，MSC 处理的 CD11c⁺细胞获得了具有增加的细胞内 IL-10 产生的调节表型。尽管与 MSC 共培养的脾细胞显示 T 细胞增殖减少和 CD4⁺FoxP3⁺调节性 T 细胞（Tregs）的扩增减少，但 CD11c⁺细胞的耗竭与 MSC 对 T 细胞的部分作用丧失有关。在体内实验中，MSCs 的肾保护作用也与诱导更不成熟的 CD11c⁺细胞和 I/R 肾脏中 FoxP3 表达增加有关。然而，当在 CD11c⁺-DTR 转基因小鼠中耗尽 CD11c⁺细胞时，MSC 诱导的所有这些作用都部分被消除。此外，观察到 WT CD11c⁺细胞的过继转移部分恢复了 MSCs 的有益作用，而转移缺乏 IL-10 的 CD11c⁺细胞则没有，这强烈表明产生 IL-10 的 CD11c⁺细胞在减轻 MSC 引起的肾损伤方面具有重要作用。我们的结果表明，CD11c⁺细胞-Tregs 在介导 MSC 的肾保护作用中起关键作用。
