MiR-154-5p regulates osteogenic differentiation of adipose-derived mesenchymal stem cells under tensile stress through the Wnt/PCP pathway by targeting Wnt11
MiR-154-5p regulates osteogenic differentiation of adipose-derived mesenchymal stem cells under tensile stress through the Wnt/PCP pathway by targeting Wnt11
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DOI：
10.1016/j.bone.2015.05.003
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发表时间：
2015-09-01
期刊：
影响因子：
4.1
通讯作者：
Long, Jie
中科院分区：
文献类型：
--
作者：
Li, Jianwei;Hu, Chen;Long, Jie
机械应力是公认的脂肪间充质干细胞（ADSCs）成骨分化的正向调控因子。然而，与微RNA（miRNAs）相关的分子机制，ADSC响应机械刺激仍然难以捉摸。我们从miRNA的角度研究了牵张应力下ADSCs成骨分化的力学转导机制。微阵列分析显示，当ADSC受到机械拉伸时，miR-154- 5 p显著下调。荧光素酶报告基因生物信息学分析表明，Wnt 11 3' UTR是miR-154- 5 p的一个新的直接靶点。在张应力下，慢病毒介导的功能获得或丧失研究显示，miR-154- 5 p的强制表达抑制了ADSCs的成骨分化，而内源性miR-154- 5 p的反义寡核苷酸（阿索-154- 5 p）抑制则明显促进了ADSCs的成骨分化。此外，miR-154- 5 p过表达降低了非经典Wnt/PCP（RhoA-ROCK）途径的活性，如miR-154- 5 p处理的ADSC中Wnt 11、活性RhoA和ROCK II表达降低所示。相反，miR-154- 5 p抑制激活Wnt/PCP信号。综上所述，这些结果表明，在拉伸应力下，miR-154- 5 p通过直接靶向Wnt 11，通过Wnt/PCP途径负调控ADSC的成骨分化。这一新的调控途径为研究ADSCs成骨分化过程中力学信号转导的分子机制提供了新的思路。(C)2015爱思唯尔公司All rights reserved.
Mechanical stress is a well-acknowledged positive regulatory factor for osteogenic differentiation of adipose-derived mesenchymal stem cells (ADSCs). However, the molecular mechanisms associated with micro-RNAs (miRNAs) whereby ADSCs respond to mechanical stimuli remain elusive. We investigated the mechanism of mechanotransduction from the miRNA perspective in the osteogenic differentiation of ADSCs under tensile stress. Microarray analysis showed that miR-154-5p was remarkably downregulated when ADSCs were subjected to mechanical tension. Bioinformatics analysis with luciferase reporter assays demonstrated that Wnt11 3' UTR was a new direct target of miR-154-5p. Under tensile stress, lentivirus-mediated gain- or loss-of-function studies revealed that forced expression of miR-154-5p inhibited osteogenic differentiation of ADSCs, whereas inhibition of endogenous miR-154-5p with its antisense oligonucleotide (ASO-154-5p) obviously promoted osteogenic differentiation. Furthermore, miR-154-5p overexpression decreased activity of the non-canonical Wnt/PCP(RhoA-ROCK) pathway, as indicated by lower expression of Wnt11, active RhoA and ROCKII in miR-154-5p-treated ADSCs. By contrast, miR-154-5p inhibition activated the Wnt/PCP signals. Taken together, these results demonstrate that, under tensile stress, miR-154-5p negatively regulates ADSCs osteogenic differentiation through the Wnt/PCP pathway by directly targeting Wnt11. This novel regulatory pathway provides new insights into the molecular mechanism of mechanotransduction in osteogenic differentiation of ADSCs. (C) 2015 Elsevier Inc. All rights reserved.