本文關(guān)鍵詞：RNA結(jié)合蛋白NOVA1調(diào)控間充質(zhì)干細(xì)胞成脂分化的作用研究　出處：《北京協(xié)和醫(yī)學(xué)院》2017年博士論文　論文類型：學(xué)位論文

  更多相關(guān)文章： 間充質(zhì)干細(xì)胞 成脂分化 神經(jīng)-腫瘤腹側(cè)抗原1 未折疊蛋白應(yīng)答反應(yīng) 多聚嘧啶束結(jié)合蛋白1 PPARγ信號通路

【摘要】：研究背景間充質(zhì)干細(xì)胞(mesenchymal stem cells,MSCs)是一類中胚層來源的具有自我更新和多向分化潛能的成體干細(xì)胞,因其組織來源廣泛、免疫原性低并具免疫調(diào)節(jié)作用而成為臨床上最具應(yīng)用前景的一類干細(xì)胞。RNA結(jié)合蛋白(RNA binding proteins,RBPs)能夠在轉(zhuǎn)錄后水平調(diào)控基因表達(dá),進(jìn)而影響細(xì)胞增殖、分化、遷移與凋亡等一系列生物學(xué)特性。NOVA1(neuro-oncological ventral antigen 1)最初被認(rèn)為是神經(jīng)特異性的RBP,對神經(jīng)細(xì)胞的存活以及發(fā)育至關(guān)重要,參與神經(jīng)突觸蛋白基因的選擇性剪接;隨后,NOVA1在腫瘤細(xì)胞和棕色脂肪發(fā)育中的作用也相繼被發(fā)現(xiàn)。我們的前期研究顯示,在人MSCs成脂分化過程中NOVA1表達(dá)升高,而NOVA1在MSCs成脂分化中的作用及其調(diào)控機(jī)制有待深入研究。研究MSCs成脂分化機(jī)制對于我們了解脂肪組織的發(fā)育、治療脂肪細(xì)胞分化失衡的疾病具有重要的理論與臨床意義。研究目的1.明確脂肪間充質(zhì)干細(xì)胞(Adipose-derived mesenchymal stem cells,ADSCs)與骨髓間充質(zhì)干細(xì)胞(Bone marrow mesenchymal stem cells,BMSCs)正常培養(yǎng)及成脂分化過程中NOVA1的動(dòng)態(tài)表達(dá)變化,并通過敲減和過表達(dá)實(shí)驗(yàn)明確NOVA1對MSCs凋亡、遷移以及成脂分化的影響。2.探討NOVA1調(diào)節(jié)MSCs成脂分化的分子機(jī)制。3.探討影響NOVA1基因表達(dá)的相關(guān)因素。研究方法和結(jié)果1.MSCs及其成脂分化過程中RBPs的表達(dá)變化方法:采用油紅O染色與茜素紅染色以及流式細(xì)胞鑒定人脂肪組織中分離的ADSCs;通過Real-time PCR檢測成脂分化過程中12個(gè)RBPs的表達(dá);采用Real-time PCR檢測人MSCs向成骨、成肌分化過程中NOVA1的表達(dá);采用免疫熒光或免疫組化的方法對ADSCs成脂分化過程和人腹部皮下脂肪組織中NOVA1蛋白表達(dá)進(jìn)行檢測;采用Real-time PCR檢測大鼠各組織中Nova1的表達(dá)。結(jié)果:分離得到人ADSCs高表達(dá)CD44、CD73、CD90、CD105等間充質(zhì)干細(xì)胞表面標(biāo)志物,不表達(dá)CD45、CD34、CD11b、CD19和HLA-DR。ADSCs成脂誘導(dǎo)過程中,hnRNPH1和PTBP1在誘導(dǎo)7天表達(dá)顯著升高;hnRNPH2、RBM38、NOVA1在誘導(dǎo)3天和7天表達(dá)均顯著升高,其中NOVA1升高程度最為明顯,而FOXC2 在誘導(dǎo) 3 天和 7 天表達(dá)降低。TIA1、TIAL1、hnRNPF、hnRNPA1、hnRNPM、FOX2在ADSCs成脂分化過程中未發(fā)生明顯變化。MSCs向成骨、成肌方向分化過程中未檢測到NOVA1的表達(dá)發(fā)生明顯變化;免疫熒光顯示,未誘導(dǎo)的ADSCs中NOVA1主要在細(xì)胞質(zhì)中表達(dá),有明顯的核質(zhì)表達(dá)區(qū)別,而在成脂誘導(dǎo)中,細(xì)胞質(zhì)和細(xì)胞核中表達(dá)均升高,核質(zhì)表達(dá)差別不明顯;人腹部皮下脂肪組織中NOVA1主要在成熟脂肪細(xì)胞的細(xì)胞核中表達(dá);基質(zhì)血管成份中NOVA1的表達(dá)遠(yuǎn)低于成熟脂肪組織;比較大鼠心臟、骨骼肌、脂肪、肝、肺、腎等組織,發(fā)現(xiàn)在脂肪組織中Nova1表達(dá)最高,骨骼肌中次之,腎中表達(dá)最低。2.NOVA1對MSCs凋亡和遷移以及成脂分化的影響方法:NOVA1敲減后采用流式細(xì)胞術(shù)檢測ADSCs凋亡情況并利用劃線法檢測其遷移能力。為了研究NOVA1對MSCs分化能力的影響,通過在MSCs中敲減和過表達(dá)NOVA1并進(jìn)行成脂誘導(dǎo),在不同時(shí)間點(diǎn)采用Real-time PCR的方法檢測成脂標(biāo)志基因的表達(dá),誘導(dǎo)7天采用油紅O染色觀察脂滴形成情況。結(jié)果:NOVA1敲減后ADSCs凋亡水平增加,遷移能力下降。敲減NOVA1抑制MSCs成脂分化,過表達(dá)NOVA1后MSCs成脂分化能力增加。過表達(dá)NOVA1后即使不添加成脂誘導(dǎo)液,7天后成脂分化標(biāo)志物ADIPOQ的表達(dá)仍升高,但未見脂滴形成。3.NOVA1在MSCs成脂分化中的作用機(jī)制方法:兩組ADSCs分別感染NOVA1敲減(shNOVA1)及對照(Scramble)慢病毒后,收取RNA并命名為shNOVA1和Scramble,另取兩組ADSCs感染NOVA1敲減及對照慢病毒后成脂誘導(dǎo)3天,收取RNA并命名為shNOVA1_A3和Scramble_A3,對四組樣本進(jìn)行全轉(zhuǎn)錄本表達(dá)譜芯片檢測以及差異基因GO分析和通路富集(pathway)分析;采用Western blot的方法對敲減NOVA1后成脂分化過程中未折疊蛋白應(yīng)答(unfolded protein response,UPR)相關(guān)蛋白表達(dá)進(jìn)行驗(yàn)證;在成脂誘導(dǎo)液中添加250nM的內(nèi)質(zhì)網(wǎng)應(yīng)激激動(dòng)劑毒胡蘿卜素(thapsigargin,TG)處理7天,與未添加TG組比較脂滴的形成以及成脂分化標(biāo)志基因的表達(dá),western blot檢測UPR相關(guān)蛋白的表達(dá);STRING網(wǎng)站對能夠與NOVA1相互作用的蛋白進(jìn)行預(yù)測,通過IP實(shí)驗(yàn)對預(yù)測到的蛋白進(jìn)行驗(yàn)證,并通過在ADSCs中敲減該蛋白后成脂誘導(dǎo),檢測成脂分化標(biāo)志基因的表達(dá)與脂滴的形成。結(jié)果:通過對Scramble_A3 vs Scramble的差異基因比較分析,發(fā)現(xiàn)參與脂質(zhì)代謝和脂質(zhì)生物合成相關(guān)基因表達(dá)差異最為明顯。對123個(gè)參與脂質(zhì)代謝的基因進(jìn)行聚類分析,發(fā)現(xiàn)在成脂誘導(dǎo)過程中明顯升高或降低的基因在敲減NOVA1后升高或降低的程度減弱。提示NOVA1參與ADSCs成脂誘導(dǎo)過程中脂質(zhì)代謝基因的表達(dá)調(diào)控。進(jìn)一步對shNOVAl_A3 vs Scramble_A3的差異基因進(jìn)行通路富集(pathway)分析,發(fā)現(xiàn)參與Unfolded Protein Response的基因表達(dá)差異最明顯,其次是PPAR信號通路。Western blot顯示參與UPR信號通路的基因在敲減NOVA1后被激活;激活內(nèi)質(zhì)網(wǎng)應(yīng)激信號抑制ADSCs成脂分化。此外,通過NOVA1結(jié)合蛋白預(yù)測以及IP結(jié)果證實(shí)NOVA1能夠與PTBP1相互結(jié)合,并且ADSCs成脂誘導(dǎo)7天PTBP1表達(dá)升高,敲減PTBP1抑制ADSCs成脂分化。4.影響MSCs成脂分化過程中NOVA1基因表達(dá)的相關(guān)因素方法:采用不同濃度的Pilocarpine和NPY處理ADSCs,在1天、3天時(shí)采用Real-time PCR的方法檢測NOVA1的表達(dá)變化;不同的成脂誘導(dǎo)成分10-6MDEX、0.5mM IBMX、10 μM Insulin、200 μM吲哚美辛、1μM羅格列酮、完全成脂誘導(dǎo)液以及添加10μM PPARy的拮抗劑GW9662的吲哚美辛、羅格列酮、完全成脂誘導(dǎo)液處理ADSCs,在1天、3天、7天時(shí)采用Real-time PCR的方法檢測NOVA1的表達(dá)變化。結(jié)果:不同濃度的Pilocarpine和NPY以及DEX和insulin對ADSCs中NOVA1的表達(dá)未見影響,IBMX在處理1天時(shí)誘導(dǎo)NOVA1表達(dá)升高,3天和7天影響不明顯;吲哚美辛在誘導(dǎo)3天和7天時(shí)可顯著促進(jìn)NOVA1表達(dá)升高;而這種促進(jìn)作用會(huì)被GW9662所抑制。研究結(jié)論1.ADSCs中表達(dá)多種RBPs,在其成脂分化過程中,hnRNPH1、PTBP1、hnRNPH2、RBM38、FOXC2、NOVA1等RBPs表達(dá)發(fā)生變化,NOVA1變化差異最明顯,而NOVA1在ADSCs成骨以及成肌分化過程中表達(dá)無顯著變化,說明NOVA1在干細(xì)胞分化中的表達(dá)具譜系特異性;NOVA在脂肪組織中的表達(dá)較在其它組織中高。提示NOVA1在脂肪分化中發(fā)揮特異性作用。2.NOVA1敲減促進(jìn)ADSCs凋亡,抑制其遷移。敲減NOVA1抑制ADSCs和BMSCs成脂分化過程中成脂相關(guān)基因的表達(dá)與脂滴的形成,過表達(dá)NOVA1則有促進(jìn)作用,說明NOVA1參與調(diào)控MSCs成脂分化;但單純過表達(dá)NOVA1不能激活MSCs的成脂分化。3.NOVA1通過作用于脂質(zhì)代謝相關(guān)基因以及UPR信號影響MSCs成脂分化,并且NOVA1可能與PTBP1作為復(fù)合體發(fā)揮作用。4.NOVA1基因啟動(dòng)子區(qū)域存在PPARy應(yīng)答元件,PPARy配體吲哚美辛和羅格列酮能夠促進(jìn)NOVA1的表達(dá),這種促進(jìn)作用可被PPARγ拮抗劑GW9662抑制,說明PPARy信號通路參與調(diào)控NOVA1的表達(dá)。
[Abstract]:The research background of mesenchymal stem cells (mesenchymal stem cells, MSCs) is a kind of mesodermal self-renewal and multilineage differentiation potential of adult stem cells, because of its organization wide source, low immunogenicity and immunomodulatory effects become clinically a kind of the most promising stem cell.RNA binding protein (RNA binding proteins, RBPs) expression in the post transcriptional regulation genes, thereby affecting cell proliferation, differentiation, migration and apoptosis and a series of biological characteristics of.NOVA1 (neuro-oncological ventral antigen 1) was initially thought to be a neural specific RBP on neuronal cell survival and development is crucial, alternative splicing in neural synaptic protein gene; subsequently, the role of NOVA1 in tumor cells and brown fat in the development have been found. Our previous studies have shown that, as a NOVA1 table fat during the differentiation process of human MSCs Increased, while NOVA1 in MSCs needs further study in the role of lipid differentiation and regulation mechanism of MSCs differentiation mechanism. Understanding of adipose tissue development for us, has important theoretical and clinical significance of treatment of fat cell differentiation imbalance diseases. Objective: 1. clear adipose derived mesenchymal stem cells (Adipose-derived mesenchymal stem cells ADSCs), and bone marrow mesenchymal stem cells (Bone marrow mesenchymal stem cells, BMSCs) expression of the dynamic changes of NOVA1 normal culture and adipogenic differentiation process, and through the knockdown and overexpression of the clear NOVA1 on MSCs apoptosis, migration and adipogenic differentiation of.2. NOVA1 MSCs.3. the molecular mechanism of lipid regulation the differentiation of the factors related to the expression of NOVA1 gene. The research methods and results of 1.MSCs and RBPs expression changes in the process of differentiation by oil red O staining and Alizarin Separation of pigment red staining and flow cytometry in human adipose tissue by ADSCs; Real-time PCR to detect the expression of 12 RBPs differentiation process; the detection of human MSCs Real-time PCR to the bone, NOVA1 expression during muscle differentiation; using the method of immunofluorescence or immunohistochemistry to detect the expression of NOVA1 protein lipid differentiation and abdominal subcutaneous fat tissue of ADSCs; the expression of Nova1 Real-time in each tissue PCR detection in rats. Results: isolated ADSCs high expression of CD44, CD73, CD90, CD105 and other mesenchymal stem cell surface markers and the expression of CD45, CD34, CD11b, CD19 and HLA-DR.ADSCs fat induced process, hnRNPH1 and PTBP1 were significantly increased in 7 days induced expression; hnRNPH2, RBM38, NOVA1 in the induction of 3 days and 7 days were significantly increased, which increased the level of NOVA1 was the most obvious, while FOXC2 induced by 3 days and 7 days decreased .TIA1, TIAL1, hnRNPF, hnRNPA1, hnRNPM, FOX2 in ADSCs did not change significantly in the process of differentiation of.MSCs into bone, muscle differentiation in the process to detect the expression of NOVA1 changed significantly; immunofluorescence showed that induced ADSCs in NOVA1 is mainly expressed in the cytoplasm, obvious nucleo cytoplasmic expression the difference, in adipogenic induction, increased expression in the cytoplasm and the nucleus, cytoplasmic expression difference was not significant; abdominal subcutaneous adipose tissue NOVA1 mainly expressed in the mature fat cell nucleus; the expression of NOVA1 in stromal vascular component is much lower than that of mature adipose tissue; rat heart, skeletal muscle, fat, liver, lung, kidney and other tissues, the highest expression of Nova1 in adipose tissue and skeletal muscle in the kidney was the lowest.2.NOVA1 on MSCs apoptosis and migration and effect method of adipogenic differentiation: knockdown of NOVA1 by flow cytometry Detection of ADSCs apoptosis and detect its migration ability by crossed method. In order to study the effect of NOVA1 on MSCs differentiation ability, through in MSCs knockdown and overexpression of NOVA1 and adipogenic induction, at different time points by using the method of Real-time PCR detection of the expression of adipogenic marker gene, induced by oil red 7 days O staining was used to observe the formation of lipid droplet increased levels of apoptosis. Results: ADSCs knockdown of NOVA1 migration decreased. Knockdown of NOVA1 inhibits adipogenic differentiation of MSCs and expression of NOVA1 MSCs after adipogenic differentiation ability increased after overexpression of NOVA1. Even if it does not add adipogenic liquid, 7 days after the expression of adipogenic differentiation marker ADIPOQ still increased, but no lipid droplet formation in the.3.NOVA1 MSCs method of mechanism of adipogenic differentiation in two groups were infected with ADSCs knockdown of NOVA1 (shNOVA1) and control (Scramble) lentivirus, charged RNA and named as shNOVA1 and Scramble, another two Knockdown of NOVA1 in ADSCs infection group and control lentivirus after adipogenic induction for 3 days, charge RNA and named as shNOVA1_A3 and Scramble_A3, four groups of samples for full transcript microarray detection and differential gene GO analysis and pathway enrichment analysis (pathway); the method of Western blot NOVA1 after the knock reduction into protein response the unfolded adipogenic differentiation process (unfolded protein response, UPR) to verify the expression of endoplasmic reticulum stress related protein; add 250nM in adipogenic medium agonist thapsigargin (thapsigargin, TG) for 7 days, and without the addition of TG group and lipid droplet formation and adipogenic differentiation marker gene expression. The expression of Western blot detection of UPR related protein; STRING site to predict to proteins that interact with NOVA1 through the IP experiment of the predicted protein was verified, and through ADSCs knockdown of the protein after adipogenic induction The guide, detection of adipogenic differentiation marker gene expression and lipid droplet formation. Results: the difference of Scramble_A3 gene vs Scramble comparative analysis, found in genes related to lipid metabolism and lipid biosynthesis in the expression of the most obvious differences. The clustering analysis of 123 genes involved in lipid metabolism were found to increase or decrease in fat in the process of induction of genes increased or decreased in NOVA1 knockdown after weaken. Expression and regulation of lipid metabolism in ADSCs suggests that NOVA1 induced adipogenic gene in the process. Further differences in groups to the shNOVAl_A3 Scramble_A3 vs (pathway) for pathway enrichment analysis, found that the expression of Protein Response gene in Unfolded the most obvious difference, followed by PPAR.Western blot showed that the signal pathway involved in UPR signaling pathway was activated in NOVA1 gene knockdown; endoplasmic reticulum stress activated signal suppression ADSCs Adipogenic differentiation. In addition, the prediction of NOVA1 binding protein and IP results show that NOVA1 can combine with PTBP1 and ADSCs expression increased 7 days induced by PTBP1 knockdown of PTBP1 lipid, inhibit the adipogenic differentiation of ADSCs.4. MSCs into factors related to expression of NOVA1 gene in the differentiation of fat methods: different concentrations of Pilocarpine and NPY ADSCs, on the 1 day, the NOVA1 expression method of Real-time PCR by 3 days; different adipogenic component 10-6MDEX, 0.5mM IBMX, 10 M Insulin, 200 M indomethacin, 1 M rosiglitazone, completely antagonist GW9662 fat induced liquid and adding 10 M PPARy of indomethacin rosiglitazone, completely adipogenic liquid treatment ADSCs, in 1 days, 3 days, the NOVA1 expression of PCR by Real-time method for 7 days. Results: different concentrations of Pilocarpine and NPY, DEX and insulin on ADSCs in the NOVA1 table No effect of IBMX, NOVA1 in the 1 day of treatment induced increased expression of 3 days and 7 days, the effect was not obvious; indomethacin can significantly promote the expression of NOVA1 increased in the induction of 3 days and 7 days; and this effect will be inhibited by GW9662. The expression of a variety of RBPs 1.ADSCs in the conclusion of the study, in the process of adipogenic differentiation in hnRNPH1, PTBP1, hnRNPH2, RBM38, FOXC2, NOVA1 and RBPs expression changes, the most obvious difference in change in NOVA1, NOVA1 and ADSCs in osteoblast and myogenic differentiation was no significant change, indicating that NOVA1 expression of stem cell differentiation with lineage specific; the expression of NOVA in adipose tissue than in in the other tissues. It suggests that NOVA1 might play a specific role of.2.NOVA1 in adipose cell differentiation knockdown promotes ADSCs apoptosis, and inhibit their migration. Knockdown of NOVA1 inhibited ADSCs and BMSCs adipogenic differentiation process of adipogenic gene expression and lipid droplet formation, overexpression of N OVA1 will have a role in promoting, indicating that NOVA1 is involved in the regulation of adipogenic differentiation of MSCs; but the simple expression of NOVA1 could not activate MSCs adipogenic differentiation of.3.NOVA1 through effects on lipid metabolism related genes UPR and MSCs signal affects the adipogenic differentiation, and NOVA1 and PTBP1 may play a role as a complex.4.NOVA1 gene promoter PPARy response element in promoter region, PPARy ligand indomethacin and rosiglitazone can promote the expression of NOVA1, this effect can be PPAR gamma antagonist GW9662 inhibited the expression of PPARy signaling pathway involved in the regulation of NOVA1.

【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R329.2

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