Promotion of the immunomodulatory properties and osteogenic differentiation of adipose-derived mesenchymal stem cells in vitro by lentivirus-mediated mir-146a sponge expression
Promotion of the immunomodulatory properties and osteogenic differentiation of adipose-derived mesenchymal stem cells in vitro by lentivirus-mediated mir-146a sponge expression
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DOI：
10.1002/term.3113
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发表时间：
2020-09-18
影响因子：
3.3
通讯作者：
Wang, Yingjun
中科院分区：
文献类型：
--
作者：
Wan, Shuangyan;Wu, Qi;Wang, Yingjun
骨髓间充质干细胞（Mesenchymal stem cells，MSCs）通过免疫调节和成骨分化对骨组织的修复具有重要作用。作为最早发现的调节先天免疫应答的miRNAs之一，miR-146 a已被报道在几种慢性炎症性疾病中充当负反馈调节剂。然而，大多数研究集中在了解miRNA-146 a如何调节免疫细胞和相关的免疫疾病。在本研究中，我们采用了使用慢病毒载体强制表达的miRNA海绵来敲低人脂肪源性干细胞（hASCs）中miR-146 a的表达。用miR-146 a海绵转导的hASC表现出增强的免疫调节特性，如关键免疫抑制因子的产生增加所证明的。这些因子能够提高巨噬细胞中抗炎基因的表达，抑制炎症基因的表达。进一步的机制研究表明，miR-146 a的抑制激活了hASCs中的NF-κ B信号，表明其在miR-146 a海绵诱导的hASCs免疫调节变化中的调节作用。此外，还发现抑制miR-146 a可刺激hASCs的成骨分化。观察到的SMAD 4表达上调表明SMAD 4参与调节hASC响应miR-146 a抑制的成骨潜力。我们的研究有助于理解miR-146 a对hASCs的免疫调节特性和成骨分化的影响，并突出了miRNA-146 a海绵修饰的hASCs作为骨组织工程种子细胞的潜在用途。
Mesenchymal stem cells (MSCs) exert beneficial effects on the repair of bone tissue via both immunomodulatory functions and osteogenic differentiation. As one of the first miRNAs identified that regulate innate immune responses, miR-146a has been reported to serve as a negative-feedback regulator in several chronic inflammatory diseases. However, the majority of studies focus on understanding how miRNA-146a regulates immune cells and the associated immune-based disorders. In the present study, we employed miRNA sponges that were forcibly expressed using a lentiviral vector to knock down the expression of miR-146a in human adipose-derived stem cells (hASCs). The hASCs transduced with miR-146a sponges exhibited enhanced immunomodulatory properties, as evidenced by the increased production of key immunosuppressive factors. These factors were able to elevated expression of anti-inflammatory genes and inhibited the expression of inflammatory genes in macrophages. Further mechanistic studies showed that the suppression of miR-146a activated NF-kappa B signaling in hASCs, suggesting its regulatory role in miR-146a sponge-induced immunomodulatory changes in hASCs. In addition, the suppression of miR-146a was also found to stimulate the osteogenic differentiation of hASCs. The observed upregulation ofSMAD4expression indicated the involvement ofSMAD4in modulating the osteogenic potential of hASCs in response to miR-146a suppression. Our study contributes to the understanding of the effects of miR-146a on the immunomodulatory properties and osteogenic differentiation of hASCs and highlights the potential use of miRNA-146a sponges modified hASCs as seed cells for bone tissue engineering.