本文選題：心肌源性microRNA(Myo-miRs) + 外泌體(exosome)�。� 參考：《華中科技大學(xué)》2015年博士論文

【摘要】：第一部分循環(huán)外泌體相關(guān)心肌源性microRNAs通過作用于CXCR4調(diào)節(jié)急性心肌梗死后骨髓干/祖細(xì)胞的動(dòng)員 [目的]心肌源性microRNAs (myocardial microRNAs, myo-miRs)在急性心肌梗死(AMl)患者的外周循環(huán)中顯著升高,但其效應(yīng)靶器官及功能學(xué)作用尚不清楚。循環(huán)中的外泌體是一類由細(xì)胞主動(dòng)性分泌的具有細(xì)胞膜結(jié)構(gòu)的小型運(yùn)輸體,能介導(dǎo)不同細(xì)胞或組織間mRNA、microRNA等遺傳物質(zhì)的交換。目前已知急性心梗能介導(dǎo)骨髓干細(xì)胞的動(dòng)員。因此,本研究擬探討急性心肌梗死后循環(huán)中升高的myo-miRs是否通過外泌體遠(yuǎn)程傳輸?shù)焦撬?從而發(fā)揮對(duì)骨髓中干/祖細(xì)胞的動(dòng)員作用。 [方法與結(jié)果]在8～10周齡雄性C57BJ/L小鼠體內(nèi)構(gòu)建急性心肌梗死模型,6小時(shí)后處死,使用實(shí)時(shí)定量PCR技術(shù)檢測(cè)四種myo-miRs (miR-1a、miR-208a、miR-133a以及miR-499-5p)在血清、血清外泌體、非外泌體血清成份、骨髓單核細(xì)胞以及其它組織中的表達(dá)水平。結(jié)果顯示急性心肌梗死6小時(shí)后myo-miRs在外泌體和非外泌體血清成份中均顯著升高；且miR-1a, miR-208a和miR-499-5p主要在外泌體中升高,而miR-133a則主要在非外泌體血清成份中升高。為了研究myo-miRs在外泌體中增高的作用,從急性心肌梗死模型小鼠的血清中分離外泌體并用PKH67標(biāo)記,通過尾靜脈注射到正常小鼠體內(nèi)；12小時(shí)后分離股骨,熒光顯微鏡檢測(cè)骨組織切片PKH67陽性的細(xì)胞,發(fā)現(xiàn)PKH67陽性的細(xì)胞存在于骨髓干骺端,提示循環(huán)中的外泌體被轉(zhuǎn)運(yùn)到了骨髓中且存在于骨髓干細(xì)胞區(qū)域。同時(shí)比較急性心肌梗死后不同組織心肌源性myo-miRs的表達(dá)水平,發(fā)現(xiàn)骨髓單核細(xì)胞中myo-miRs表達(dá)量顯著高于肝,腎,脾,說明循環(huán)中的myo-miRs主要被轉(zhuǎn)運(yùn)到骨髓中。下一步,分別將急性心梗分離的外泌體和非外泌體血清成份跟骨髓單核細(xì)胞共培養(yǎng),發(fā)現(xiàn)只有外泌體共培養(yǎng)的骨髓單核細(xì)胞中myo-miRs的表達(dá)增高,說明主要是由外泌體介導(dǎo)了循環(huán)中myo-miRs向骨髓單核細(xì)胞的轉(zhuǎn)運(yùn)oSDF-1/CXCR4信號(hào)通路在骨髓干細(xì)胞動(dòng)員中起重要作用。在體外轉(zhuǎn)染myo-miRs的特異性化學(xué)模擬物(microRNA mimics)到骨髓單核細(xì)胞中,發(fā)現(xiàn)這四種myo-miR均對(duì)CXCR4有明顯抑制作用。而后,將急性心梗小鼠體內(nèi)分離的外泌體與骨髓單核細(xì)胞共培養(yǎng),證明了急性心梗相關(guān)外泌體能夠顯著抑制骨髓單核細(xì)胞內(nèi)CXCR4的表達(dá);而當(dāng)myo-miRs被抑制后,急性心梗相關(guān)外泌體對(duì)CXCR4的調(diào)節(jié)作用明顯減弱。為了進(jìn)一步驗(yàn)證急性心梗分泌的外泌體是否介導(dǎo)了骨髓干細(xì)胞的動(dòng)員,在小鼠體內(nèi)靜脈注射急性心肌梗外泌體及正常對(duì)照外泌體,結(jié)果發(fā)現(xiàn)在急性心肌梗死外泌體處理的小鼠外周血中Lin-、c-kit+及c-kit+Lin-的細(xì)胞顯著增多,提示急性心梗分泌的外泌體能夠介導(dǎo)骨髓干細(xì)胞的動(dòng)員。 [結(jié)論]綜上所述,急性心肌梗死外周循環(huán)中升高的myo-miRs,通過外泌體轉(zhuǎn)運(yùn)骨髓單核細(xì)胞中,抑制骨髓干細(xì)胞中CXCR4表達(dá),從而介導(dǎo)骨髓干/祖細(xì)胞動(dòng)員。本研究為干細(xì)胞治療提供了新的潛在靶點(diǎn)。 第二部分急性心肌梗死相關(guān)血清外泌體miR-1通過CX3CR1調(diào)節(jié)骨髓間充質(zhì)干細(xì)胞的遷移 [目的]急性心肌梗死后,缺血心肌分泌大量心肌特異性的microRNA到外周循環(huán)中。文獻(xiàn)報(bào)道,急性心梗后循環(huán)中miR-1顯著增高,但是循環(huán)中的miR-1是如何被轉(zhuǎn)運(yùn)及其生物作用目前還不清楚。外泌體是一類由細(xì)胞主動(dòng)性分泌的具有細(xì)胞膜結(jié)構(gòu)的小型運(yùn)輸體,能介導(dǎo)不同細(xì)胞或組織間mRNA以及micRNA等遺傳物質(zhì)的交換。CX3CR1是一個(gè)在骨髓間充質(zhì)干細(xì)胞中豐富表達(dá)的趨化因子受體,CX3CR1/Fractalkine信號(hào)通路對(duì)于骨髓間充質(zhì)干細(xì)胞的向缺血損傷組織趨化具有重要調(diào)節(jié)作用。本研究旨在探索急性心肌梗死后血清中的心肌源性miR-1是否通過外泌體形式被釋放,以及其對(duì)骨髓間充質(zhì)干細(xì)胞中CX3CR1的潛在調(diào)節(jié)作用。 [方法與結(jié)果]在雄性SD大鼠體內(nèi)構(gòu)建急性心肌梗死模型,收集對(duì)照組以及急性心梗組的大鼠外周血清并從中提取出血清外泌體,使用實(shí)時(shí)定量PCR技術(shù)檢測(cè)各組血清以及血清外泌體中miR-1的表達(dá)水平。結(jié)果發(fā)現(xiàn),急性心肌梗死組中miR-1在血清中顯著增高,這跟文獻(xiàn)報(bào)道一致。同時(shí)還發(fā)現(xiàn),miR-1在血清外泌體中的增高水平顯著高于非外泌體血清成份,提示循環(huán)中miR-1主要存在于外泌體中。為了進(jìn)一步研究血清外泌體miR-1對(duì)骨髓間充質(zhì)干細(xì)胞的調(diào)節(jié)作用,在體外培養(yǎng)誘導(dǎo)SD大鼠的骨髓間充質(zhì)干細(xì)胞,并將急性心梗的血清外泌體進(jìn)行熒光標(biāo)記后與骨髓間充質(zhì)干細(xì)胞進(jìn)行共培養(yǎng),熒光顯微鏡的觀察發(fā)現(xiàn)骨髓間充質(zhì)干細(xì)胞能夠有效攝取血清外泌體。此外,還將急性心肌梗死后6小時(shí)分離的血清外泌體與骨髓間充質(zhì)干細(xì)胞共培養(yǎng),通過實(shí)時(shí)定量PCR技術(shù)證明急性心梗相關(guān)血清外泌體能夠顯著上調(diào)骨髓間充質(zhì)干細(xì)胞內(nèi)的miR-1的表達(dá)水平。為探討血清外泌體miR-1轉(zhuǎn)運(yùn)到骨髓間充質(zhì)干細(xì)胞內(nèi)潛在的生物學(xué)作用,在骨髓間充質(zhì)干細(xì)胞中轉(zhuǎn)染miR-1的特異性化學(xué)模擬物,實(shí)時(shí)定量PCR技術(shù)和蛋白印跡技術(shù)檢測(cè)表明miR-1可以明顯下調(diào)骨髓間充質(zhì)干細(xì)胞內(nèi)CX3CR1的mRNA和蛋白質(zhì)的表達(dá)水平,同時(shí),還通過體外遷移實(shí)驗(yàn)證明miR-1顯著抑制了骨髓間充質(zhì)干細(xì)胞向fractalkine的趨化作用。 [結(jié)論]綜上所述,大鼠體內(nèi)急性心肌梗死相關(guān)血清外泌體miR-1具有下調(diào)骨髓間充質(zhì)干細(xì)胞內(nèi)CX3CR1表達(dá)水平并抑制骨髓間充質(zhì)干細(xì)胞趨化能力的潛能,這一現(xiàn)象將有可能成為骨髓間充質(zhì)干細(xì)胞治療心臟缺血性損傷的新靶點(diǎn)。
[Abstract]:Part 1 circulating exocrine related cardiac derived microRNAs modulates the mobilization of bone marrow stem / progenitor cells after CXCR4 in acute myocardial infarction.
[Objective] myocardial derived microRNAs (myocardial microRNAs, myo-miRs) is significantly elevated in the peripheral circulation of patients with acute myocardial infarction (AMl), but the effect of its target organ and function is not clear. The exocrine in the circulation is a small transporter, which is secreted by cells, and can mediate different cells or different cells. It is known that acute myocardial infarction can mediate the mobilization of bone marrow stem cells. Therefore, this study intends to explore whether or not the elevated myo-miRs in the post infarction cycle is transmitted to the bone marrow through the exocrine after acute myocardial infarction, so as to mobilize the stem / progenitor cells in the bone marrow.
[methods and results] an acute myocardial infarction model was constructed in 8~10 weeks old male C57BJ/L mice and executed after 6 hours. Real-time quantitative PCR was used to detect the expression of four kinds of myo-miRs (miR-1a, miR-208a, miR-133a and miR-499-5p) in serum, serum exocrine, non exocrine serum components, bone marrow mononuclear cells and other tissues. The results showed that myo-miRs increased significantly in both exocrine and non exocrine serum levels after 6 hours of acute myocardial infarction, and miR-1a, miR-208a and miR-499-5p increased mainly in the exocrine, while miR-133a increased mainly in the non exocrine serum components. In order to study the increase of myo-miRs in the exocrine, acute myocardial infarction was from acute myocardial infarction. The sera of the dead model mice were separated and labeled with PKH67, and the femur was injected into the normal mice by the tail vein. After 12 hours, the femur was separated and the PKH67 positive cells were detected by the fluorescence microscope. It was found that the PKH67 positive cells existed in the metaphysis of the bone marrow, suggesting that the exocrine in the circle was transported to the bone marrow and existed in the bone marrow. At the same time, the expression level of cardiac myo-miRs in different tissues after acute myocardial infarction was compared. The expression of myo-miRs in bone marrow mononuclear cells was significantly higher than that of liver, kidney and spleen, indicating that the myo-miRs in the circulation was mainly transported to the bone marrow. The next step was to separate the exocrine and non exocrine serum from the acute myocardial infarction. It was found that the expression of myo-miRs in bone marrow mononuclear cells increased in only exocrine co cultured mononuclear cells, indicating that the exocrine mediated transport of myo-miRs to bone marrow mononuclear cells in the circulation plays an important role in the mobilization of bone marrow stem cells. The specific transfection of myo-miRs in vitro is specific. In microRNA mimics to bone marrow mononuclear cells, the four myo-miR were found to have a significant inhibitory effect on CXCR4. Then, the exosbodies isolated from the acute myocardial infarction mice and bone marrow mononuclear cells were co cultured, which proved that the acute myocardial infarction related exocrine could significantly inhibit the expression of CXCR4 in the mononuclear cells of the bone marrow; and when myo-m In order to further verify whether the exocrine secreted by acute myocardial infarction mediates the mobilization of bone marrow stem cells in order to further verify that the exocrine secreted by acute myocardial infarction mediates the mobilization of the bone marrow stem cells, the acute myocardial infarction is administered by intravenous injection of acute myocardial infarction and normal exocrine in mice, and the fruit is now treated with acute myocardial infarction outside the iRs. The Lin-, c-kit+ and c-kit+Lin- cells in the peripheral blood of mice increased significantly, suggesting that exocrine secreted by acute myocardial infarction can mediate the mobilization of bone marrow stem cells.
[Conclusion] to sum up, myo-miRs, which is elevated in the peripheral circulation of acute myocardial infarction, can inhibit the expression of CXCR4 in bone marrow stem cells through exosomatic transport of bone marrow mononuclear cells and mediate the mobilization of bone marrow stem / progenitor cells. This study provides a new potential target for stem cell therapy.
The second part of the acute myocardial infarction related serum exocrine miR-1 regulates the migration of bone marrow mesenchymal stem cells through CX3CR1.
[Objective] after acute myocardial infarction, the ischemic myocardium secretes a large number of myocardium specific microRNA to peripheral circulation. It is reported that miR-1 is significantly increased in the posterior circulation of acute myocardial infarction, but it is not clear how the miR-1 in the circulation is transported and its biological effect is still unclear. The exocrine is a cell membrane structure secreted by cell activity. The small transporter, which mediates the exchange of genetic material such as mRNA and micRNA between different cells or tissues, is a chemokine receptor rich in bone marrow mesenchymal stem cells. The CX3CR1/Fractalkine signaling pathway plays an important role in the chemotaxis of bone marrow mesenchymal stem cells to ischemic tissue. The purpose of this study is to investigate the effect of.CX3CR1 on the chemotaxis of bone marrow mesenchymal stem cells. In the exploration of acute myocardial infarction, the release of cardiac miR-1 in the serum through the form of exocrine and its potential regulation of CX3CR1 in bone marrow mesenchymal stem cells.
[methods and results] the acute myocardial infarction model was constructed in the male SD rats. The peripheral serum of the rats in the control group and the acute myocardial infarction group were collected and the haemorrhagic exocrine was extracted from the rats. The expression of miR-1 in the serum and the serum exocrine was detected by real-time quantitative PCR technique. The results showed that the miR-1 in the acute myocardial infarction group was in the acute myocardial infarction group. The serum levels were significantly higher, which was consistent with the literature. At the same time, it was found that the increase of miR-1 in the serum exocrine was significantly higher than that of the non exocrine serum, suggesting that miR-1 mainly existed in the exocrine. In order to further study the regulation of serum exocrine miR-1 on bone marrow mesenchymal stem cells, the induction of SD in vitro was large. The rat bone marrow mesenchymal stem cells were cultured with bone marrow mesenchymal stem cells after fluorescence labeling of acute myocardial infarction. The fluorescence microscopy showed that bone marrow mesenchymal stem cells could effectively absorb the serum exocrine. In addition, the serum exocrine and bone marrow were separated 6 hours after acute myocardial infarction. Coculture of stromal cells, through real-time quantitative PCR technique, demonstrated that acute myocardial infarction related serum exocrine could significantly increase the level of miR-1 expression in bone marrow mesenchymal stem cells, and to explore the potential biological role of serum exocrine miR-1 transport to bone marrow mesenchymal stem cells, and the specific transfection of miR-1 in bone marrow mesenchymal stem cells. The chemical mimics, real-time quantitative PCR and Western blot assays showed that miR-1 could obviously reduce the level of mRNA and protein expression of CX3CR1 in bone marrow mesenchymal stem cells. At the same time, in vitro migration experiments showed that miR-1 significantly inhibited the chemotaxis of bone marrow mesenchymal stem cells to fractalkine.
[Conclusion] to sum up, the acute myocardial infarction related serum exosomatic miR-1 in rats has the potential to downregulate the expression of CX3CR1 in bone marrow mesenchymal stem cells and inhibit the chemotaxis of bone marrow mesenchymal stem cells. This phenomenon may be a new target for the treatment of cardiac ischemic injury by bone marrow mesenchymal stem cells.
【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2015
【分類號(hào)】：R542.2

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