miR-21 Modulates the Immunoregulatory Function of Bone Marrow Mesenchymal Stem Cells Through the PTEN/Akt/TGF-β1 Pathway
miR-21 Modulates the Immunoregulatory Function of Bone Marrow Mesenchymal Stem Cells Through the PTEN/Akt/TGF-β1 Pathway
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miR-21通过PTEN/Akt/TGF-β1途径调节骨髓间充质干细胞的免疫调节功能
DOI：
10.1002/stem.2081
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发表时间：
2015-11-01
期刊：
影响因子：
5.2
通讯作者：
Wang, Songlin
中科院分区：
文献类型：
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作者：
Wu, Tingting;Liu, Yi;Wang, Songlin
microRNA（miRNAs）作为维持间充质干细胞（MSCs）的干性、自我更新和分化的调节信号，但miRNAs是否调节MSCs的免疫调节功能仍不清楚。在这里，我们表明，miR-21负调节免疫调节细胞因子转化生长因子-β 1（TGF-β 1）在MSC的活性。一致地，来自miR-21（-/-）小鼠的骨髓间充质干细胞（BMMSC）通过更多的TGF-β 1分泌显示增强的免疫抑制功能，并且与抗TGF-β 1抗体废除的野生型BMMSC相比，在体外诱导更多的CD 4（+）Foxp 3（+）调节性T细胞。在机制上，miR-21通过靶向BMMSC中10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）来抑制TGF-β 1表达。在PTEN下游，miR-21促进Akt的活化，从而增加NF-κ B通路的活化。重要的是，将miR-21（-/-）BMMSC过继转移到患有实验性结肠炎的小鼠中以TGF-β 1依赖性方式更有效地改善结肠炎症。因此，这些发现表明先前未揭示的miR-21通过TGF-β 1抑制来控制BMMSC的免疫调节功能的机制。
microRNAs (miRNAs) act as regulatory signals for maintaining stemness, self-renewal, and differentiation of mesenchymal stem cells (MSCs), but whether miRNAs modulate the immunoregulatory function of MSCs remains largely unknown. Here, we show that miR-21 negatively regulates the activity of immunoregulatory cytokine transforming growth factor-beta 1 (TGF-beta 1) in MSCs. Consistently, bone marrow MSCs (BMMSCs) from miR-21(-/-) mice show enhanced immunosuppressive function by more TGF-beta 1 secretion and induce more CD4(+)Foxp3(+) regulatory T cells compared with wild-type BMMSCs in vitro, which anti-TGF-beta 1 antibody abrogates. Mechanistically, miR-21 inhibits TGF-beta 1 expression by targeting phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in BMMSCs. Downstream of PTEN, miR-21 promotes activation of Akt, and consequently increases activation of NF-kappa B pathway. Importantly, adoptive transfer of miR-21(-/-) BMMSCs into mice with experimental colitis more effectively ameliorates colonic inflammation in a TGF-beta 1-dependent manner. Thus, these findings indicate a previously uncovered mechanism of miR-21 control immunoregulatory function of BMMSCs through TGF-beta 1 inhibition.