Effects of miR-146a on the osteogenesis of adipose-derived mesenchymal stem cells and bone regeneration.
Effects of miR-146a on the osteogenesis of adipose-derived mesenchymal stem cells and bone regeneration.
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miR-146a对脂肪间充质干细胞成骨及骨再生的影响
DOI：
10.1038/srep42840
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发表时间：
2017-02-16
影响因子：
4.6
通讯作者：
Fan X
中科院分区：
文献类型：
--
作者：
Xie Q;Wei W;Ruan J;Ding Y;Zhuang A;Bi X;Sun H;Gu P;Wang Z;Fan X
越来越多的证据表明，骨形态发生蛋白2（BMP 2）与microRNAs（miRNAs）协同形成细胞内网络，调控间充质干细胞（MSCs）的成骨作用。本研究旨在鉴定BMP 2诱导的大鼠脂肪间充质干细胞（ADSCs）成骨过程中的特异性miRNA，并选取其中下调最显著的miRNA miR-146 a，系统研究其在成骨和骨再生中的调控作用。过表达miR-146 a显著抑制ADSC成骨，而敲低miR-146 a则大大促进了这一过程。果蝇母体抗十肢麻痹蛋白4（SMAD 4）是BMP信号通路中的重要辅激活因子，是miR-146 a的直接靶点，miR-146 a通过与SMAD 4 mRNA的3′-非翻译区（3′-UTR）相互作用而发挥对SMAD 4的抑制作用。此外，敲低SMAD 4减弱了miR-146 a抑制剂促进ADSC成骨的能力。接下来，将转导的ADSC与聚（癸二酰甘油二酯）（PSeD）多孔支架结合用于修复临界尺寸的颅骨缺损，miR-146 a抑制剂的处理极大地增强了ADSC介导的骨再生，在新形成的骨中具有更高的SMAD 4、Runt相关转录因子2（Runx 2）和Osterix表达水平。综上所述，我们的研究表明miR-146 a在体外和体内均对ADSCs的成骨和骨再生具有负调控作用。
Increasing evidence has indicated that bone morphogenetic protein 2 (BMP2) coordinates with microRNAs (miRNAs) to form intracellular networks regulating mesenchymal stem cells (MSCs) osteogenesis. This study aimed to identify specific miRNAs in rat adipose-derived mesenchymal stem cells (ADSCs) during BMP2-induced osteogenesis, we selected the most significantly down-regulated miRNA, miR-146a, to systematically investigate its role in regulating osteogenesis and bone regeneration. Overexpressing miR-146a notably repressed ADSC osteogenesis, whereas knocking down miR-146a greatly promoted this process. Drosophila mothers against decapentaplegic protein 4 (SMAD4), an important co-activator in the BMP signaling pathway, was miR-146a’s direct target and miR-146a exerted its repressive effect on SMAD4 through interacting with 3′-untranslated region (3′-UTR) of SMAD4 mRNA. Furthermore, knocking down SMAD4 attenuated the ability of miR-146a inhibitor to promote ADSC osteogenesis. Next, transduced ADSCs were incorporated with poly(sebacoyl diglyceride) (PSeD) porous scaffolds for repairing critical-sized cranial defect, the treatment of miR-146a inhibitor greatly enhanced ADSC-mediated bone regeneration with higher expression levels of SMAD4, Runt-related transcription factor 2 (Runx2) and Osterix in newly formed bone. In summary, our study showed that miR-146a negatively regulates the osteogenesis and bone regeneration from ADSCs bothin vitroandin vivo.