高脂环境下miR-29c-3p靶向调节Dvl2对BMSCs成骨分化机制研究
发布时间：2019-06-29 16:40
【摘要】：研究背景:高脂血症是动脉粥样硬化、骨质疏松、高血压、冠心病、脑卒中等疾病发生、发展的重要危险因素,是目前影响人民群众身体健康的高发疾病之一。研究表明高脂血症对骨愈合、骨矿化、骨密度等诸多骨代谢过程有不良影响,高脂血症是引起骨质疏松的危险因素之一。在骨髓间充质干细胞(bone marrow stromal stem cells,BMSCs)向成骨细胞定向分化中Wnt信号通路起关键性作用。而最近几年大量的研究表明,成骨的分化过程中微小RNA(microRNAs,miRNAs)发挥了重要的生物学功能,例如维持骨代谢的平衡。本课题组前期实验证实高脂饲料喂养的大鼠种植体周围骨质疏松,骨小梁稀疏,排列紊乱;高脂饲料喂养的大鼠种植体周围Ca/P原子个数百分比低于普通饲料喂养的大鼠;荧光定量PCR和Western blot结果显示Dvl2基因、Dvl2蛋白的表达受到抑制,表明高脂血症在一定程度上干扰高脂血症大鼠种植体的早期骨结合。Wnt/β-catenin信号通路中的Dvl2在高脂血症患者中具体如何发挥作用值得探讨。Wnt信号通路与miRNAs存在大量的交叉信号分子,其作用靶点与具体作用机制都值得深入探讨研究。实验目的:(1)观察高脂环境下大鼠骨髓基质干细胞(BMSCs)成骨分化过程中Runx2、ALP、SP7、PPAR-γ、Dvl2及靶向调控Dvl2相关microRNAs的mRNA表达。(2)利用靶基因预测软件、双荧光素酶报告基因筛选及鉴定出靶向调节Dvl2的microRNAs。(3)探讨microRNAs靶向调节Dvl2对BMSCs成骨分化的影响。实验方法:(1)大鼠骨髓间充质干细胞获取传代培养,培养第三代时行流式细胞检测,分别成骨成脂诱导28天后茜素红和油红O染色,观察成骨成脂分化能力,鉴定BMSCs,以便用于后续实验。用高脂培养基和普通培养基成骨诱导BMSCs诱导28天时分别行茜素红和油红O染色观察成骨分化情况,诱导3、5、7、14、21天,利用RT-PCR检测细胞内成骨相关基因Runx2、ALP、SP7,成脂相关基因PPAR-γ,Wnt信号通路中Dvl2,与靶向调控Dvl2相关的miR-21-5p、miR-29c-3p、miR-138-5p、miR-351-5pmRNA的表达。(2)靶向调控Dvl2相关的microRNAs采用靶基因预测软件Target Scan、MicroRNA.org、miRDB、Microcosm Targets 等四种 miRNA 数据库在线分析软件进行生物信息学预测,以及文献查询,得到可能与Dvl2基因3'UTR区作用的 miRNAs 为:miR-21-5p、miR-29c-3p、miR-138-5p、miR-351-5p。通过体外转染不同浓度(10nm、30nm、50nm、100nm)梯度的FAM-siRNA,6h后镜下观察转染效率和CCK8检测其细胞增殖筛选合适的转染浓度。利用筛选浓度体外转染 miR-21-5p、miR-29c-3p、miR-138-5p、miR-351-5p 的模拟物(mimics)和抑制物(inhibitor),48h后利用RT-PCR检测转染效率,实现Dvl2的过表达和低表达,Western blot检测BMSCs中Dvl2的表达差异,找出引起Dvl2变化最明显的miRNA。构建双荧光素酶报告基因质粒载体,分别用 miR-21-5p、miR-29c-3p、miR-138-5p、miR-351-5p 的模拟物与质粒载体共转293t细胞,利用多功能酶标仪检测荧光素酶活性,验证miRNAs与Dvl2的靶向调控作用。(3)高脂环境下体外转染miR-29c-3p mimics和inhibitor后成骨诱导BMSCs 3、7天,利用Western bolt检测成骨相关基因Runx2、ALP的表达情况。实验结果:(1)流式细胞仪检测结果显示:第三代BMSCs CD44阳性细胞比率是96.7%,CD45阳性细胞比率是2.8%,CD90阳性细胞比率是95.9%。间充质干细胞表面标志抗原表达阳性,验证此细胞为BMSCs,纯度较高。成骨诱导28天茜素红染色、油红O染色结果显示BMSCs具有向成骨成脂方向分化能力。培养28天茜素红染色见高脂组较对照组钙化结节少,油红O染色串珠样脂滴高脂组多于对照组,RT-PCR结果显示成骨指标Runx2、SP7、ALPmRNA表达高脂组较对照组低,成脂指标PPAR-γ mRNA表达高脂组较对照组高,差异有统计学意义(P0.05)。miR-21-5p、miR-29c-3p高脂组较对照组均降低,在3、5、7、14天时miR-138-5pmRNA表达量对照组与高脂组无明显差异,在21天时miR-138-5pmRNA表达量对照组明显高于高脂组,差异有显著意义(P0.05)。在3、5、7天时miR-351-5pmRNA表达量对照组与高脂组无明显差异,在14、21天时miR-351-5pmRNA表达量对照组低于高脂组,差异有显著意义。(2)荧光显微镜观察浓度越高转染效率越高,CCK8浓度越高细胞增殖越受到抑制,Real-time PCR 结果显示,转染 miR-21-5p、miR-29c-3p、miR-138-5p、miR-351-5p的mimics后,与对照组相比其表达量分别升高5-6倍、4倍、1000倍和800倍左右。而转染相应的inhibitor后,与对照组相比其表达量分别降低约3倍、10倍、10倍和5倍。转染miR-21-5p、miR-29c-3p、miR-138-5p、miR-351-5p 的 mimics 和 inhibitor 及 NC48h 后,RT-PCR 结果显示,转染 miR-21-5p 和 miR-29c-3p mimics 后,与 mimics nc 组相比 Dvl2的表达降低,转染 miR-138-5p 和 miR-351-5p mimics 后,与 mimics nc 组相比 Dvl2 的表达升高。转染 miR-21-5p、miR-29c-3p、miR-138-5p、miR-351-5p inhibitor后与inhibitor nc组相比Dvl2的表达都有不同程度的升高。Western blot结果显示,miR-29c-3pmimics/inhibitor转染细胞后,Dvl2表达差异最明显。(3)Western blot 结果显示转染 miR-29c-3p mimics 后 Runx2 和 ALP 的蛋白表达水平均明显比mimics NC组增高,转染inhibitor后Runx2和ALP的蛋白表达水平均明显比inhibitor NC组降低。结论:(1)高脂环境下BMSCs向成骨细胞分化减少,miR-21-5p、miR-29c-3p、miR-138-5p、miR-351-5p参与调控高脂环境下骨代谢和成骨细胞的生物学活性。(2)经双荧光素酶报告基因筛选及鉴定出靶向调节Dvl2的miRNA是miR-29c-3p,而miR-21-5p、miR-138-5p、miR-351-5p对Dvl2的负性调节作用弱。(3)miR-29c-3p通过靶向调节Dvl2间接促进BMSCs向成骨分化、矿化能力。
[Abstract]:Background: Hyperlipemia is an important risk factor for the occurrence and development of atherosclerosis, osteoporosis, hypertension, coronary heart disease, and stroke. It is one of the most frequent diseases that affect the health of the people. The results show that the hyperlipoidemia has an adverse effect on bone metabolism, bone mineralization, bone mineral density and other bone metabolism, and it is one of the risk factors for osteoporosis. Bone marrow mesenchymal stem cells (BMSCs) play a critical role in the directional differentiation of bone marrow mesenchymal stem cells (BMSCs) into the osteoblast-oriented differentiation. In recent years, a large number of studies have shown that microRNAs (microRNAs, miRNAs) play an important biological function in the differentiation of osteogenesis, such as maintaining a balance of bone metabolism. In the early stage of the research group, the rats with high-fat diet were proved to be loose, the bone trabecula is sparse and the arrangement is disordered; the percentage of Ca/ P atoms in the peripheral Ca/ P atoms in the rat implant fed by the high-fat feed is lower than that of the normal feed-fed rats; and the fluorescence quantitative PCR and the Western blot result show that the Dvl2 gene, The expression of the Dvl2 protein is inhibited, indicating that the hyperlipidemia can interfere with the early bone combination of the hyperlipidemic rat implant to a certain extent. The role of Dvl2 in the Wnt/ HCO3-cattenin signal pathway in patients with hyperlipidemia is worth exploring. The Wnt signaling pathway and miRNAs have a large number of cross-signal molecules, and the action target and the specific action mechanism of the Wnt signal pathway are worth exploring deeply. Objective: (1) To observe the expression of Runx2, ALP, SP7, PPAR-1, Dvl2 and targeted regulation of Dvl2-related microRNAs in rat bone marrow stromal stem cells (BMSCs) in high-fat environment. And (2) screening and identifying the microRNAs targeting the Dvl2 by using the target gene prediction software and the double-luciferase reporter gene. (3) To investigate the effect of microRNAs targeting regulation of Dvl2 on the osteogenic differentiation of BMSCs. Methods: (1) The rat bone marrow-derived mesenchymal stem cells were collected and cultured, and the flow cytometry was carried out in the third generation. After 28 days of formation of the bone marrow-derived mesenchymal stem cells, the bone marrow-derived mesenchymal stem cells were cultured for 28 days, respectively, and stained with red and red O-red O, and the osteogenic differentiation ability was observed, and BMSCs were identified for subsequent experiments. The osteogenesis and differentiation of BMSCs were observed with high-fat medium and normal medium for 28 days, and the osteogenic differentiation was observed in 3,5,7,14 and 21 days by RT-PCR, and the expression of Dvl2, ALP, SP7, lipoid-related gene PPAR-1 and Wnt in Wnt signaling pathway was detected by RT-PCR. The expression of miR-21-5p, miR-29c-3p, miR-138-5p, and miR-351-5pmRNA associated with targeted regulation of Dvl2. (2) The target gene prediction software, Target Scan, MicroRNA.org, miRDB, Microcosm Targets and other four miRNA database on-line analysis software is used for bioinformatics prediction and the literature query to obtain the miRNAs that can function with the Dvl2 gene 3 'UTR region as the miR-21-5p, the miR-29c-3p, the miR-138-5p, and the miR-351-5p. The transfection efficiency and the cell proliferation of CCK8 were detected by transfecting the FAM-siRNA with different concentration (10 nm,30 nm,50 nm,100 nm) in vitro. Transfection of miR-21-5p, miR-29c-3p, miR-138-5p, miR-351-5p and the inhibitor in vitro with the screening concentration, the transfection efficiency was detected by RT-PCR after 48 h, the overexpression and low expression of Dvl2 were achieved, and the expression of Dvl2 in BMSCs was detected by Western blot, and the most obvious miRNAs were found. The plasmid vector of the two-luciferase reporter gene was constructed, and the 293T cells were co-transferred with the plasmid vector by the miRNAs-21-5p, the miR-29c-3p, the miR-138-5p, and the miR-351-5p, and the activity of the luciferase was detected by the multi-function microplate reader to verify the targeting and control effects of miRNAs and Dvl2. (3) The expression of bone-related gene Runx2 and ALP was detected by Western blot. Results: (1) The results of flow cytometry showed that the ratio of CD44 positive cells in third generation BMSCs was 96.7%, the ratio of CD45 positive cells was 2.8%, and the ratio of CD90 positive cells was 95.9%. The surface marker antigen of the mesenchymal stem cells is positive, and the cell is BMSCs, and the purity is high. The results showed that BMSCs had the ability to differentiate into the direction of osteogenesis. The results of RT-PCR showed that the expression of Runx2, SP7 and ALPmRNA in the high-fat group was lower than that in the control group, and the expression of PPAR-mRNA in the high-fat group was higher than that of the control group. The difference was significant (P0.05). The miR-21-5p, miR-29c-3p high-fat group and the control group were decreased, and the expression of miR-138-5 pmRNA in the 3,5,7 and 14 days was not significantly different from that in the high-fat group, and the expression of miR-138-5 pmRNA in the control group was significantly higher than that of the control group at 21 days (P0.05). At 3,5 and 7 days, the expression of miR-351-5pmRNA in the control group was not significantly different from that of the high-fat group, and the expression of miR-351-5pmRNA in the control group was lower than that of the control group at 14 and 21 days, and the difference was significant. (2) The higher the observation concentration of the fluorescence microscope, the higher the efficiency of the transfection, the higher the concentration of the CCK8, the higher the proliferation of the cells. The real-time PCR results showed that the expression of the miR-21-5p, the miR-29c-3p, the miR-138-5p, and the miR-351-5p increased by 5-6 times,4-fold,1000-fold and 800-fold, respectively, as compared to the control group. Compared with the control group, the expression was about 3-fold,10-fold,10-fold and 5-fold, respectively. The expression of Dvl2 in miR-21-5p, miR-29c-3p, miR-138-5p, miR-351-5p, miR-138-5p, miR-351-5p was reduced after transfection of miR-21-5p and miR-29c-3p misitics, and the expression of Dvl2 was increased compared to the mimics nc group after the transfection of miR-138-5p and miR-351-5p mmics. The expression of Dvl2 in miR-21-5p, miR-29c-3p, miR-138-5p, and miR-351-5p inhimitor was increased in different degrees after transfection. The results of Western blot showed that the expression of Dvl2 was the most obvious after the transfection of the cells with miR-29c-3pmomics/ inhitor. (3) The results of Western blot show that the level of protein expression of both Runx2 and ALP after transfection of miR-29c-3p mmics is significantly higher than that of the mimics NC group. Conclusion: (1) In high-fat environment, BMSCs differentiated into osteoblasts, miR-21-5p, miR-29c-3p, miR-138-5p, and miR-351-5p participate in the control of the biological activity of bone metabolism and osteoblast in high-fat environment. (2) The miRNAs targeted to the regulation of Dvl2 are miR-29c-3p, and miR-21-5p, miR-138-5p, and miR-351-5p are weak in negative regulation of Dvl2. (3) miR-29c-3p indirectly promotes the differentiation and mineralization of BMSCs by targeting and regulating Dvl2.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R589.2;R580
本文编号：2507960
[Abstract]:Background: Hyperlipemia is an important risk factor for the occurrence and development of atherosclerosis, osteoporosis, hypertension, coronary heart disease, and stroke. It is one of the most frequent diseases that affect the health of the people. The results show that the hyperlipoidemia has an adverse effect on bone metabolism, bone mineralization, bone mineral density and other bone metabolism, and it is one of the risk factors for osteoporosis. Bone marrow mesenchymal stem cells (BMSCs) play a critical role in the directional differentiation of bone marrow mesenchymal stem cells (BMSCs) into the osteoblast-oriented differentiation. In recent years, a large number of studies have shown that microRNAs (microRNAs, miRNAs) play an important biological function in the differentiation of osteogenesis, such as maintaining a balance of bone metabolism. In the early stage of the research group, the rats with high-fat diet were proved to be loose, the bone trabecula is sparse and the arrangement is disordered; the percentage of Ca/ P atoms in the peripheral Ca/ P atoms in the rat implant fed by the high-fat feed is lower than that of the normal feed-fed rats; and the fluorescence quantitative PCR and the Western blot result show that the Dvl2 gene, The expression of the Dvl2 protein is inhibited, indicating that the hyperlipidemia can interfere with the early bone combination of the hyperlipidemic rat implant to a certain extent. The role of Dvl2 in the Wnt/ HCO3-cattenin signal pathway in patients with hyperlipidemia is worth exploring. The Wnt signaling pathway and miRNAs have a large number of cross-signal molecules, and the action target and the specific action mechanism of the Wnt signal pathway are worth exploring deeply. Objective: (1) To observe the expression of Runx2, ALP, SP7, PPAR-1, Dvl2 and targeted regulation of Dvl2-related microRNAs in rat bone marrow stromal stem cells (BMSCs) in high-fat environment. And (2) screening and identifying the microRNAs targeting the Dvl2 by using the target gene prediction software and the double-luciferase reporter gene. (3) To investigate the effect of microRNAs targeting regulation of Dvl2 on the osteogenic differentiation of BMSCs. Methods: (1) The rat bone marrow-derived mesenchymal stem cells were collected and cultured, and the flow cytometry was carried out in the third generation. After 28 days of formation of the bone marrow-derived mesenchymal stem cells, the bone marrow-derived mesenchymal stem cells were cultured for 28 days, respectively, and stained with red and red O-red O, and the osteogenic differentiation ability was observed, and BMSCs were identified for subsequent experiments. The osteogenesis and differentiation of BMSCs were observed with high-fat medium and normal medium for 28 days, and the osteogenic differentiation was observed in 3,5,7,14 and 21 days by RT-PCR, and the expression of Dvl2, ALP, SP7, lipoid-related gene PPAR-1 and Wnt in Wnt signaling pathway was detected by RT-PCR. The expression of miR-21-5p, miR-29c-3p, miR-138-5p, and miR-351-5pmRNA associated with targeted regulation of Dvl2. (2) The target gene prediction software, Target Scan, MicroRNA.org, miRDB, Microcosm Targets and other four miRNA database on-line analysis software is used for bioinformatics prediction and the literature query to obtain the miRNAs that can function with the Dvl2 gene 3 'UTR region as the miR-21-5p, the miR-29c-3p, the miR-138-5p, and the miR-351-5p. The transfection efficiency and the cell proliferation of CCK8 were detected by transfecting the FAM-siRNA with different concentration (10 nm,30 nm,50 nm,100 nm) in vitro. Transfection of miR-21-5p, miR-29c-3p, miR-138-5p, miR-351-5p and the inhibitor in vitro with the screening concentration, the transfection efficiency was detected by RT-PCR after 48 h, the overexpression and low expression of Dvl2 were achieved, and the expression of Dvl2 in BMSCs was detected by Western blot, and the most obvious miRNAs were found. The plasmid vector of the two-luciferase reporter gene was constructed, and the 293T cells were co-transferred with the plasmid vector by the miRNAs-21-5p, the miR-29c-3p, the miR-138-5p, and the miR-351-5p, and the activity of the luciferase was detected by the multi-function microplate reader to verify the targeting and control effects of miRNAs and Dvl2. (3) The expression of bone-related gene Runx2 and ALP was detected by Western blot. Results: (1) The results of flow cytometry showed that the ratio of CD44 positive cells in third generation BMSCs was 96.7%, the ratio of CD45 positive cells was 2.8%, and the ratio of CD90 positive cells was 95.9%. The surface marker antigen of the mesenchymal stem cells is positive, and the cell is BMSCs, and the purity is high. The results showed that BMSCs had the ability to differentiate into the direction of osteogenesis. The results of RT-PCR showed that the expression of Runx2, SP7 and ALPmRNA in the high-fat group was lower than that in the control group, and the expression of PPAR-mRNA in the high-fat group was higher than that of the control group. The difference was significant (P0.05). The miR-21-5p, miR-29c-3p high-fat group and the control group were decreased, and the expression of miR-138-5 pmRNA in the 3,5,7 and 14 days was not significantly different from that in the high-fat group, and the expression of miR-138-5 pmRNA in the control group was significantly higher than that of the control group at 21 days (P0.05). At 3,5 and 7 days, the expression of miR-351-5pmRNA in the control group was not significantly different from that of the high-fat group, and the expression of miR-351-5pmRNA in the control group was lower than that of the control group at 14 and 21 days, and the difference was significant. (2) The higher the observation concentration of the fluorescence microscope, the higher the efficiency of the transfection, the higher the concentration of the CCK8, the higher the proliferation of the cells. The real-time PCR results showed that the expression of the miR-21-5p, the miR-29c-3p, the miR-138-5p, and the miR-351-5p increased by 5-6 times,4-fold,1000-fold and 800-fold, respectively, as compared to the control group. Compared with the control group, the expression was about 3-fold,10-fold,10-fold and 5-fold, respectively. The expression of Dvl2 in miR-21-5p, miR-29c-3p, miR-138-5p, miR-351-5p, miR-138-5p, miR-351-5p was reduced after transfection of miR-21-5p and miR-29c-3p misitics, and the expression of Dvl2 was increased compared to the mimics nc group after the transfection of miR-138-5p and miR-351-5p mmics. The expression of Dvl2 in miR-21-5p, miR-29c-3p, miR-138-5p, and miR-351-5p inhimitor was increased in different degrees after transfection. The results of Western blot showed that the expression of Dvl2 was the most obvious after the transfection of the cells with miR-29c-3pmomics/ inhitor. (3) The results of Western blot show that the level of protein expression of both Runx2 and ALP after transfection of miR-29c-3p mmics is significantly higher than that of the mimics NC group. Conclusion: (1) In high-fat environment, BMSCs differentiated into osteoblasts, miR-21-5p, miR-29c-3p, miR-138-5p, and miR-351-5p participate in the control of the biological activity of bone metabolism and osteoblast in high-fat environment. (2) The miRNAs targeted to the regulation of Dvl2 are miR-29c-3p, and miR-21-5p, miR-138-5p, and miR-351-5p are weak in negative regulation of Dvl2. (3) miR-29c-3p indirectly promotes the differentiation and mineralization of BMSCs by targeting and regulating Dvl2.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R589.2;R580
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