Exosomal miR-146a Contributes to the Enhanced Therapeutic Efficacy of Interleukin-1-Primed Mesenchymal Stem Cells Against Sepsis
Exosomal miR-146a Contributes to the Enhanced Therapeutic Efficacy of Interleukin-1-Primed Mesenchymal Stem Cells Against Sepsis
复制标题
外泌体 miR-146a 有助于增强白细胞介素 1 引发的间充质干细胞对抗脓毒症的疗效
DOI：
10.1002/stem.2564
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发表时间：
2017-05-01
期刊：
影响因子：
5.2
通讯作者：
Hou, Yayi
中科院分区：
文献类型：
--
作者：
Song, Yuxian;Dou, Huan;Hou, Yayi
通过促炎细胞因子预处理提高间充质干细胞（MSCs）的免疫调节功效是一个不断发展的研究领域。然而，其潜在机制尚未完全阐明。在这里，我们用白细胞介素-1 （IL-1）预处理人脐带来源的MSCs，并在盲肠结扎和穿刺性脓毒症模型中评估其治疗效果。我们发现，与未处理的MSCs相比，系统给药il -1预处理的MSCs （MSCs）更有效地改善了小鼠败血症的症状，并提高了存活率。此外，MSCs可以通过旁分泌活性更有效地诱导巨噬细胞向抗炎M2表型极化。在机制上，我们证明了骨髓间充质干细胞衍生的外泌体有助于增强骨髓间充质干细胞在体外和体内的免疫调节特性。重要的是，我们发现miR-146a，一种众所周知的抗炎microRNA，在IL-1刺激下被强烈上调，并被选择性地包装到外泌体中。这种外泌体miR-146a被转移到巨噬细胞中，导致M2极化，最终导致脓毒症小鼠的存活率提高。相反，通过转染miR-146a抑制剂抑制miR-146a，部分地否定了msc来源的外泌体的免疫调节特性。综上所述，IL-1预处理部分通过外泌体介导的miR-146a的转移有效地增强了MSCs的免疫调节特性。因此，我们认为IL-1预处理可能为MSCs在炎症性疾病中的更好的治疗应用提供了一种新的模式。茎Cells2017;35:1208 - 1221
Improving the immunomodulatory efficacy of mesenchymal stem cells (MSCs) through pretreatment with pro-inflammatory cytokines is an evolving field of investigation. However, the underlying mechanisms have not been fully clarified. Here, we pretreated human umbilical cord-derived MSCs with interleukin-1 (IL-1) and evaluated their therapeutic effects in a cecal ligation and puncture-induced sepsis model. We found that systemic administration of IL-1-pretreated MSCs (MSCs) ameliorated the symptoms of murine sepsis more effectively and increased the survival rate compared with naive MSCs. Furthermore, MSCs could more effectively induce macrophage polarization toward an anti-inflammatory M2 phenotype through the paracrine activity. Mechanistically, we demonstrated that MSC-derived exosomes contributed to the enhanced immunomodulatory properties of MSCs both in vitro and in vivo. Importantly, we found that miR-146a, a well-known anti-inflammatory microRNA, was strongly upregulated by IL-1 stimulation and selectively packaged into exosomes. This exosomal miR-146a was transferred to macrophages, resulted in M2 polarization, and finally led to increased survival in septic mice. In contrast, inhibition of miR-146a through transfection with miR-146a inhibitors partially negated the immunomodulatory properties of MSC-derived exosomes. Taken together, IL-1 pretreatment effectively enhanced the immunomodulatory properties of MSCs partially through exosome-mediated transfer of miR-146a. Therefore, we believe that IL-1 pretreatment may provide a new modality for better therapeutic application of MSCs in inflammatory disorders. Stem Cells2017;35:1208-1221