miR-20调控人骨髓来源的间充质干细胞成骨分化及机理研究
发布时间：2018-07-15 11:43
【摘要】：人骨髓来源的间充质干细胞(MSCs)是一种具有多向分化能力的干细胞,在一些分化因子的调控下能分化成多种细胞,如成脂细胞、成骨细胞、成软骨细胞等。所以,MSCs作为成骨细胞的前体细胞,对于骨的形成和重建具有重要的意义。 microRNA(miRNA)是由20 ~ 24个核苷酸组成的非编码小RNA,可以通过与靶标基因mRNA 3’-UTR上的靶点结合,介导mRNA降解或抑制mRNA转录后水平的表达,从而导致靶标蛋白表达的下降。近十年来的研究发现miRNA在胚胎发育及细胞的增殖、分化和凋亡等多种生命活动中发挥着重要作用。但是,miRNA是否调控MSCs成骨分化的命运却一直未见报道。 我们在研究中发现,miR-17-5p家族,尤其是miR-20a,能决定人MSCs成骨分化的命运和调控成骨分化的过程。miR-20a mimics的过表达能促进Runx2和BMPs在转录和翻译水平的表达升高,从而激活BMP信号通路。我们通过软件预测和分析,发现PPARγ是miR-20a的一个靶标基因。miR-20a能通过抑制PPARγ表达来上调Runx2和BMPs的表达,从而破坏成脂分化与成骨分化的动态平衡,决定MSCs成骨分化的命运。软件的预测还提示BAMBI和CRIM1也是它的靶标基因。其中BAMBI是BMP的一个假受体,与真受体竞争性的与BMP蛋白结合,从而拮抗BMP信号通路。而CRIM1是BMP信号通路的抑制子,能阻断BMP蛋白的成熟和向细胞膜的转移。所以,miR-20a通过抑制这两个基因的表达从而上调了BMP信号通路,而BMP信号的激活又加速了成骨分化。总之,本论文研究发现miR-20a通过调控靶标基因PPARγ的表达决定了MSCs成骨分化的命运,又通过对另外两个靶标基因BAMBI和CRIM1的表达抑制从而上调了BMP/Runx2信号通路。
[Abstract]:Human bone marrow-derived mesenchymal stem cells (MSCs) are multidirectional stem cells, which can differentiate into many kinds of cells under the control of some differentiation factors, such as adipoblast, osteoblast, chondroblast and so on. As a precursor of osteoblasts, MSCs are important for bone formation and reconstruction. MicroRNA (miRNA) is a small non-coding RNAs composed of 20 ~ 24 nucleotides, which can be combined with target sites of target gene mRNA 3nc-UTR. It mediates mRNA degradation or inhibits the expression of mRNA posttranscriptional level, which leads to the decrease of target protein expression. In recent ten years, miRNA has been found to play an important role in embryonic development, cell proliferation, differentiation and apoptosis. However, whether miRNA regulates the osteogenic differentiation of MSCs has not been reported. We found that miR-17-5p family, especially miR-20a, can determine the fate of osteogenic differentiation of human MSCs and regulate the process of osteogenic differentiation. The overexpression of miR-20a mimics can promote the expression of Runx2 and BMPs at transcription and translation level, thus activating the BMPsignaling pathway. Through software prediction and analysis, we found that PPAR 纬 is a target gene of miR-20a. MiR-20a can up-regulate the expression of Runx2 and BMPs by inhibiting the expression of PPAR 纬, thus disrupting the dynamic balance between adipogenic and osteogenic differentiation and determining the fate of osteogenic differentiation of MSCs. Software predictions also suggest that BAMBI and CRIM1 are also its target genes. Among them, BAMBI is a pseudoreceptor of BMP, which binds to BMP protein competitively with true receptor, thus antagonizing BMP signaling pathway. CRIM1 is an inhibitor of BMP signaling pathway, which can block the maturation of BMP protein and its transfer to cell membrane. Therefore, miR-20a upregulated the BMP signaling pathway by inhibiting the expression of these two genes, and the activation of BMP signal accelerated osteogenic differentiation. In conclusion, we found that miR-20a determines the osteogenic differentiation of MSCs by regulating the expression of target gene PPAR 纬, and up-regulates the BMPP Runx2 signaling pathway by inhibiting the expression of other two target genes BAMBI and CRIM1.
【学位授予单位】：清华大学
【学位级别】：博士
【学位授予年份】：2010
【分类号】：R329
本文编号：2123949
[Abstract]:Human bone marrow-derived mesenchymal stem cells (MSCs) are multidirectional stem cells, which can differentiate into many kinds of cells under the control of some differentiation factors, such as adipoblast, osteoblast, chondroblast and so on. As a precursor of osteoblasts, MSCs are important for bone formation and reconstruction. MicroRNA (miRNA) is a small non-coding RNAs composed of 20 ~ 24 nucleotides, which can be combined with target sites of target gene mRNA 3nc-UTR. It mediates mRNA degradation or inhibits the expression of mRNA posttranscriptional level, which leads to the decrease of target protein expression. In recent ten years, miRNA has been found to play an important role in embryonic development, cell proliferation, differentiation and apoptosis. However, whether miRNA regulates the osteogenic differentiation of MSCs has not been reported. We found that miR-17-5p family, especially miR-20a, can determine the fate of osteogenic differentiation of human MSCs and regulate the process of osteogenic differentiation. The overexpression of miR-20a mimics can promote the expression of Runx2 and BMPs at transcription and translation level, thus activating the BMPsignaling pathway. Through software prediction and analysis, we found that PPAR 纬 is a target gene of miR-20a. MiR-20a can up-regulate the expression of Runx2 and BMPs by inhibiting the expression of PPAR 纬, thus disrupting the dynamic balance between adipogenic and osteogenic differentiation and determining the fate of osteogenic differentiation of MSCs. Software predictions also suggest that BAMBI and CRIM1 are also its target genes. Among them, BAMBI is a pseudoreceptor of BMP, which binds to BMP protein competitively with true receptor, thus antagonizing BMP signaling pathway. CRIM1 is an inhibitor of BMP signaling pathway, which can block the maturation of BMP protein and its transfer to cell membrane. Therefore, miR-20a upregulated the BMP signaling pathway by inhibiting the expression of these two genes, and the activation of BMP signal accelerated osteogenic differentiation. In conclusion, we found that miR-20a determines the osteogenic differentiation of MSCs by regulating the expression of target gene PPAR 纬, and up-regulates the BMPP Runx2 signaling pathway by inhibiting the expression of other two target genes BAMBI and CRIM1.
【学位授予单位】：清华大学
【学位级别】：博士
【学位授予年份】：2010
【分类号】：R329
【引证文献】
相关硕士学位论文 前1条
1 郭杰;MicroRNA-370在高频脉冲电磁场下对骨髓间充质干细胞增值调控作用的初步研究[D];广西医科大学;2013年
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