本文關(guān)鍵詞： 內(nèi)皮祖細(xì)胞 Foxc2 CXCR4 遷移 粘附 歸巢 募集 再內(nèi)皮化 新生內(nèi)膜增生　出處：《華中科技大學(xué)》2011年博士論文　論文類型：學(xué)位論文

【摘要】：內(nèi)皮損傷或功能障礙是動(dòng)脈粥樣硬化和血管成形術(shù)后再狹窄等心血管疾病發(fā)生進(jìn)展的始動(dòng)環(huán)節(jié)。加快損傷內(nèi)皮的修復(fù)可有效抑制新生內(nèi)膜的增生,對(duì)動(dòng)脈粥樣硬化的早期預(yù)防和血管成形術(shù)后再狹窄的防治具有重要意義。 近年的研究表明動(dòng)員或移植的內(nèi)皮祖細(xì)胞(endothelial progenitor cells, EPCs)可直接分化為內(nèi)皮細(xì)胞,和或以旁分泌機(jī)制刺激成熟內(nèi)皮增殖遷移,促進(jìn)損傷血管的再內(nèi)皮化,抑制新生內(nèi)膜的增生。充足的歸巢是移植EPCs功能發(fā)揮的前提,但大多數(shù)動(dòng)物及臨床實(shí)驗(yàn)顯示移植EPCs的歸巢和長(zhǎng)期植入率都非常低,這也是導(dǎo)致治療效果不理想的重要原因之一。事實(shí)上,EPCs在損傷區(qū)歸巢聚集的數(shù)量不僅取決于循環(huán)中細(xì)胞數(shù)目也取決于移植細(xì)胞遷移粘附等生物學(xué)功能。有研究表明CXCR4的表達(dá)水平對(duì)EPCs的歸巢及促內(nèi)皮修復(fù)功能起重要的調(diào)控作用。然而,冠心病的危險(xiǎn)因素可導(dǎo)致EPCs CXCR4表達(dá)下調(diào)或CXCR4的信號(hào)通路受損,導(dǎo)致EPCs的遷移歸巢能力下降,嚴(yán)重影響了EPCs移植的療效。因此,CXCR4表達(dá)及功能調(diào)控已成為EPCs治療領(lǐng)域重要的研究課題。 Foxc2蛋白是叉頭框轉(zhuǎn)錄因子家族成員之一,對(duì)于心血管系統(tǒng)起重要的調(diào)控作用。在胚胎發(fā)育期,Foxc2可以調(diào)控內(nèi)皮基因表達(dá)及血管的發(fā)生。近來研究表明Foxc2可通過多個(gè)環(huán)節(jié)調(diào)控血管生成。例如,Foxc2可誘導(dǎo)多種粘附分子和促血管生成因子的表達(dá)。此外,Foxc2可直接調(diào)控內(nèi)皮細(xì)胞CXCR4的表達(dá)。然而Foxc2對(duì)EPCs生物學(xué)特性的影響,迄今尚未見報(bào)道�；诖�,我們欲探討Foxc2對(duì)EPCs CXCR4表達(dá)、歸巢功能及促內(nèi)皮修復(fù)效應(yīng)的影響。本研究分為三個(gè)部分。 第一部分小鼠骨髓內(nèi)皮祖細(xì)胞的培養(yǎng)及鑒定 目的：分離培養(yǎng)小鼠骨髓源內(nèi)皮祖細(xì)胞并鑒定。 方法：分離小鼠骨髓單個(gè)核細(xì)胞,在內(nèi)皮培養(yǎng)系定向誘導(dǎo)培養(yǎng)15-21天,通過形態(tài)學(xué)觀察細(xì)胞的生長(zhǎng)形態(tài),用免疫熒光、Western blot及流式細(xì)胞儀技術(shù)檢測(cè)內(nèi)皮標(biāo)記及造血系標(biāo)記,Dil-acLDL攝取及Matrigel管樣結(jié)構(gòu)形成實(shí)驗(yàn)檢測(cè)內(nèi)皮分化的功能學(xué)特性。 結(jié)果：分離骨髓單個(gè)核細(xì)胞誘導(dǎo)培養(yǎng)14天后,培養(yǎng)細(xì)胞逐漸呈現(xiàn)單層的“鋪路石樣”外觀。免疫熒光檢測(cè)結(jié)果顯示,絕大多數(shù)細(xì)胞表達(dá)內(nèi)皮標(biāo)記物CD31、VE-cadherin及vWF; Western blot分析進(jìn)一步證實(shí)培養(yǎng)細(xì)胞表達(dá)內(nèi)皮標(biāo)記FLK-1、CD31和VE-cadherin。而流式細(xì)胞儀分析顯示培養(yǎng)細(xì)胞幾乎不表達(dá)造血系標(biāo)記CD34和CD45. Dil-acLDL攝取結(jié)果顯示,約95%的細(xì)胞吸收Dil-acLDL。Matrigel管狀結(jié)構(gòu)形成實(shí)驗(yàn)顯示培養(yǎng)細(xì)胞能圍成管狀、網(wǎng)絡(luò)狀結(jié)構(gòu)。因此,從形態(tài)學(xué)、細(xì)胞表型及功能學(xué)鑒定來看,培養(yǎng)細(xì)胞具有內(nèi)皮集落形成細(xì)胞(endothelial colony forming cells, ECFCs)或晚期EPCs特性。 結(jié)論：小鼠骨髓單個(gè)核細(xì)胞在特定誘導(dǎo)擴(kuò)增的培養(yǎng)條件下可獲得EPCs。 第二部分Foxc2過表達(dá)對(duì)內(nèi)皮祖細(xì)胞遷移及粘附能力的影響 目的：研究Foxc2過表達(dá)對(duì)EPCs體外遷移及粘附功能的影響及其機(jī)制。 方法：將PcDNA3.1-Foxc2質(zhì)粒用脂質(zhì)體轉(zhuǎn)染EPCs,轉(zhuǎn)染48小時(shí)后用定量RT-PCR及Western blot檢鋇Foxc2基因的表達(dá)。用免疫熒光、Western blot、流式細(xì)胞儀及定量RT-PCR方法檢測(cè)CXCR4的表達(dá)。用Transwell小室檢測(cè)EPCs向SDF-1α遷移,用靜止粘附實(shí)驗(yàn)檢測(cè)EPCs與纖維連接蛋白的粘附。 結(jié)果：定量RT-PCR及Western blot檢測(cè)結(jié)果顯示,PcDNA3.1-Foxc2質(zhì)粒轉(zhuǎn)染顯著增加Foxc2 mRNA及蛋白的表達(dá)。免疫熒光、Western blot及流式細(xì)胞儀結(jié)果表明Foxc2過表達(dá)增加EPCs CXCR4蛋白的表達(dá),定量RT-PCR檢測(cè)顯示Foxc2-EPCs CXCR4 mRNA水平大約是對(duì)照組的2倍(P＜0.05)。在SDF-1α刺激下,Foxc2-EPCs遷移及粘附能力明顯高于Ctrl-EPCs,而AMD3100或LY294002可抑制Foxc2-EPCs增加的遷移及粘附效應(yīng)。 結(jié)論：Foxc2過表達(dá)能有效增加EPCs CXCR4的表達(dá)及體外遷移、粘附功能,Foxc2過表達(dá)所增強(qiáng)的遷移及粘附效應(yīng)與CXCR4表達(dá)上調(diào)及下游PI3K/Akt信號(hào)活化增強(qiáng)有關(guān)。 第三部分Foxc2過表達(dá)對(duì)內(nèi)皮祖細(xì)胞歸巢及促內(nèi)皮修復(fù)作用的影響 目的：研究Foxc2過表達(dá)對(duì)EPCs體內(nèi)歸巢及促內(nèi)皮修復(fù)作用的影響。 方法：建立小鼠頸動(dòng)脈內(nèi)膜損傷模型。從野生小鼠和GFP小鼠骨髓分離培養(yǎng)EPCs和GFP/EPCs,進(jìn)行Foxc2質(zhì)粒轉(zhuǎn)染,再經(jīng)尾靜脈輸注頸動(dòng)脈內(nèi)膜損傷小鼠體內(nèi),3天后觀察損傷部位GFP標(biāo)記細(xì)胞數(shù)目,以檢測(cè)移植EPCs在體內(nèi)歸巢潛能；7天后用Evens藍(lán)染色檢測(cè)損傷血管再內(nèi)皮化的程度,14天后觀察GFP+內(nèi)皮細(xì)胞的百分比,以檢測(cè)移植GFP/EPCs摻入修復(fù)內(nèi)皮層的情況,28天后組織學(xué)檢測(cè)新生內(nèi)膜和中膜面積的比值(N／M),評(píng)價(jià)EPCs移植抑制新生內(nèi)膜增生的治療效應(yīng)。 結(jié)果：GFP/EPCs移植3天后,GFP+嚴(yán)格局限于損傷部位的腔表面,Foxc2-GFP/EPCs移植組損傷血管募集的GFP+細(xì)胞明顯多于Ctrl-GFP/EPCs組(約為Ctrl-GFP/EPCs組的2倍,P＜0.05)；7天后,Ctrl-EPCs移植組損傷血管再內(nèi)皮化程度明顯提高,Foxc2-EPCs組再內(nèi)皮化程度又顯著高于Ctrl-EPCs組(90.3±1.6%vs 57.2±1.3%,P＜0.05)；14天后,Foxc2-GFP/EPCs移植組GFP+內(nèi)皮細(xì)胞百分比顯著高于Ctrl-GFP/EPCs組(46.67±7.09%vs 31.50±5.26%,P＜0.05)；28天后,Ctrl-EPCs移植組小鼠損傷血管新生內(nèi)膜的形成明顯減少,N／M較PBS組降低了65%,而Foxc2-EPCs組新生內(nèi)膜的增生程度降低更明顯(N／M：0.38±0.03 vs 0.67±0.05,P＜0.05)。最后,Foxc2-EPCs移植前用AMD3100或LY294002預(yù)孵育能顯著抑制Foxc2過表達(dá)所增強(qiáng)的EPCs歸巢能力、促進(jìn)再內(nèi)皮化及抑制新生內(nèi)膜增生的效應(yīng)。 結(jié)論：Foxc2過表達(dá)可促進(jìn)EPCs在損傷內(nèi)膜的歸巢和募集,相應(yīng)提高EPCs促內(nèi)皮修復(fù)及抑制新生內(nèi)膜增生的效應(yīng)；而且Foxc2過表達(dá)增強(qiáng)的EPCs歸巢及治療效應(yīng)與CXCR4/PI3K/Akt信號(hào)通路有關(guān)。
[Abstract]:Endothelial injury or dysfunction is the initiating factor in atherosclerosis and restenosis after angioplasty and other cardiovascular diseases. To accelerate the repair of endothelial injury can effectively inhibit neointimal hyperplasia, plays an important role in the prevention and early vascular angioplasty on atherosclerosis prevention after the narrow narrow again.
Recent studies suggest that mobilization or transplantation of endothelial progenitor cells (endothelial progenitor cells, EPCs) can directly differentiate into endothelial cells, and to stimulate or paracrine mechanism of mature endothelial proliferation and migration, promote reendothelialization, inhibition of neointimal hyperplasia. The homing sufficient is a prerequisite for transplantation of EPCs function, but most of the animal and clinical experiments showed that the homing EPCs transplantation and long-term implantation rate is very low, this is one of the important reasons causing the treatment effect is not ideal. In fact, EPCs in the damage zone homing aggregation number depends not only on the number of circulating cell transplantation depends on cell adhesion and migration and other biological functions. Studies have shown that expression of homing the level of CXCR4 and EPCs on promoting endothelial repair function plays an important role. However, the risk factors of coronary heart disease can lead to EPCs CXCR4 expression or CXCR4 letter The damage of pathway has led to the decrease of migration and homing ability of EPCs, which seriously affects the efficacy of EPCs transplantation. Therefore, CXCR4 expression and function regulation have become an important research topic in the field of EPCs treatment.
Foxc2 protein is a forkhead box transcription factor family, the cardiovascular system plays an important role. In the stage of embryonic development, Foxc2 can regulate endothelial gene expression and angiogenesis. Recent studies have shown that Foxc2 can regulate angiogenesis through multiple links. For example, Foxc2 can induce the expression of adhesion molecules and angiogenesis factor. In addition, the expression of Foxc2 can directly regulate endothelial cell CXCR4. The influence of Foxc2 on the biological characteristics of EPCs, however, has not been reported so far. Based on this, we want to explore the effect of Foxc2 on the expression of EPCs CXCR4, the homing function and the promotion of endothelial repair effect. This research is divided into three parts.
The culture and identification of bone marrow endothelial progenitor cells in the first part of mice
Objective: to isolate and culture the mouse bone marrow derived endothelial progenitor cells and identify them.
Methods: the isolation of bone marrow mononuclear cells, cultured and induced for 15-21 days of orientation in endothelial morphology was observed by morphology, immunofluorescence and Western blot detection of endothelial markers and flow cytometry hematopoietic markers, Dil-acLDL uptake and Matrigel tube formation assay function and endothelial differentiation characteristics.
Results: the separation of bone marrow mononuclear cells induced by cultured cells after 14 days of culture, gradually showing a cobblestone like appearance. Immunofluorescence showed that most cells express endothelial markers CD31, VE-cadherin and vWF; Western blot analysis further confirmed the cultured cells expressed endothelial markers FLK-1, CD31 and VE-cadherin. and flow cytometry. Instrument analysis showed that the cultured cells were almost not expressed hematopoietic markers CD34 and CD45. Dil-acLDL uptake showed that about 95% of the cells to absorb Dil-acLDL.Matrigel tube formation experiments showed that the cultured cells can form tubular network structure. Therefore, the morphology, phenotype and functional identification, cultured cells with endothelial colony forming cells (endothelial colony forming cells, ECFCs) or late EPCs characteristics.
Conclusion: the mouse bone marrow mononuclear cells can obtain EPCs. under specific induced culture conditions.
The effect of overexpression of Foxc2 on the migration and adhesion of endothelial progenitor cells in the second part
Objective: To study the effect of overexpression of Foxc2 on the migration and adhesion of EPCs in vitro and its mechanism.
Methods: PcDNA3.1-Foxc2 plasmid were transfected into EPCs, 48 hours after transfection with RT-PCR and Western blot expression quantitative detecting Foxc2 gene. By immunofluorescence, Western blot, flow cytometry and quantitative RT-PCR method to detect CXCR4. Detected by Transwell chamber EPCs to SDF-1 with alpha migration, adhesion of EPCs and fibronectin detection the static adhesion experiment.
Results: RT-PCR and Western quantitative blot assay showed that transfection of PcDNA3.1-Foxc2 plasmid significantly increased the expression of Foxc2 mRNA and protein. Immunofluorescence, Western blot and flow cytometry showed that Foxc2 overexpression increased the expression of EPCs CXCR4 protein, Foxc2-EPCs CXCR4 display quantitative RT-PCR detection of mRNA level is about 2 times that of the control group (P < 0.05). In SDF-1 stimulation, Foxc2-EPCs migration and adhesion ability was significantly higher than that of Ctrl-EPCs, migration and adhesion effect while AMD3100 or LY294002 can inhibit the Foxc2-EPCs increase.
Conclusion: Foxc2 overexpression can effectively increase EPCs CXCR4 expression and migration in vitro, and adhesion function. The enhanced migration and adhesion effect of Foxc2 overexpression is related to the up regulation of CXCR4 expression and the enhancement of downstream PI3K/Akt signal activation.
The effect of overexpression of Foxc2 on endothelial progenitor cell homing and endothelial repair in the third part
Objective: To study the effect of overexpression of Foxc2 on homing and endothelial repair in EPCs in vivo.
Methods: to establish a mouse model of carotid artery intimal injury. EPCs and GFP/EPCs were isolated and cultured from bone marrow of wild-type mice and GFP mice were transfected with Foxc2 plasmid, followed by intravenous injection of carotid intimal injury in mice was observed after 3 days, the number of injured parts of GFP labeled cells to detect the potential of EPCs transplantation in vivo homing; 7 days later by Evens the degree of blue staining detection of vascular endothelial injury, after 14 days of observation GFP+ percentage of endothelial cells, to detect transplanted GFP/EPCs incorporation repair endothelial layer, the ratio of detection of neointima and media area 28 days after the organization (N / M), to evaluate the curative effect of EPCs transplantation inhibits neointimal hyperplasia.
Results: GFP/EPCs 3 days after transplantation, cavity surface GFP+ strictly confined to the site of injury, injury of vascular Foxc2-GFP/EPCs transplantation group raised significantly more GFP+ cells than Ctrl-GFP/EPCs group (about 2 times that of the Ctrl-GFP/EPCs group P < 0.05); 7 days later, Ctrl-EPCs transplantation group reendothelialization significantly improved, Foxc2-EPCs group recellularization the degree was significantly higher than the Ctrl-EPCs group (90.3 + 57.2 1.6%vs + 1.3%, P < 0.05); 14 days later, Foxc2-GFP/EPCs transplantation group GFP+ endothelial cell percentage was significantly higher than that of Ctrl-GFP/EPCs group (46.67 + 31.50 7.09%vs + 5.26%, P < 0.05); 28 days later, the formation of Ctrl-EPCs mice of transplantation group neointimal / N decreased obviously. M was 65% lower than in PBS group, Foxc2-EPCs group and the degree of hyperplasia of neointima was reduced (N / M:0.38 + 0.03 vs 0.67 + 0.05, P < 0.05). Finally, using AMD3100 or LY294002 pre Foxc2-EPCs before transplantation Incubation can significantly inhibit the EPCs homing ability of Foxc2 over expression, promote re endothelialization and inhibit the effect of neointimal hyperplasia.
Conclusion: over expression of Foxc2 can promote the homing and recruitment of EPCs in injured intima, and enhance the effect of EPCs on endothelial repair and neointimal hyperplasia. Foxc2 overexpression enhances EPCs homing and its therapeutic effect is related to CXCR4/PI3K/Akt signaling pathway.

【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】：2011
【分類號(hào)】：R363

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2 王s，

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