本文選題：間充質(zhì)干細(xì)胞 + 腦微血管內(nèi)皮細(xì)胞��； 參考：《第三軍醫(yī)大學(xué)》2008年碩士論文

【摘要】： 研究背景: 骨髓間充質(zhì)干細(xì)胞(mesenchymal stem cells, MSC)是來源于骨髓的成體干細(xì)胞,具有多潛能分化性,已證明MSC修復(fù)和分化為多種組織的能力,尤其在修復(fù)和重建血管方面成為缺血性疾病治療研究的熱點(diǎn)。腦微血管內(nèi)皮細(xì)胞(brain microvascular endothelial cells, BMEC)是構(gòu)成血腦屏障的最主要組成部分,具有細(xì)胞間緊密連接、極少的胞飲囊泡和維持神經(jīng)組織離子和代謝穩(wěn)定的特殊跨膜轉(zhuǎn)運(yùn)系統(tǒng)等獨(dú)有生理特點(diǎn)。在缺血性腦血管疾病中,BMEC的損傷是導(dǎo)致血腦屏障開放、腦水腫發(fā)生,從而加重神經(jīng)元細(xì)胞損傷的重要因素,同時(shí)缺血半暗區(qū)腦微血管的修復(fù)與新生也是挽救缺血受損神經(jīng)元的關(guān)鍵。當(dāng)前,在干細(xì)胞治療缺血性腦血管病的研究方面,多數(shù)研究聚焦于干細(xì)胞修復(fù)受損的神經(jīng)組織,然而在干細(xì)胞對(duì)腦缺血部位受損的血腦屏障和微血管內(nèi)皮細(xì)胞影響的研究并未深入。本實(shí)驗(yàn)以缺氧條件下培養(yǎng)BMEC模擬缺血性腦血管疾病中血腦屏障和腦微血管所處的病理生理環(huán)境,觀察BMEC對(duì)共培養(yǎng)的MSC分化的影響,以及MSC以旁分泌方式對(duì)BMEC增殖、遷移和血腦屏障模型通透性的影響,為MSC應(yīng)用于缺血性腦血管疾病的治療提供基礎(chǔ)實(shí)驗(yàn)依據(jù)。 研究目的: 1.分離、培養(yǎng)及鑒定大鼠BMEC和人骨髓MSC,建立缺氧條件下BMEC與MSC直接與間接共培養(yǎng)的模型,觀察缺氧條件下BMEC對(duì)直接與間接共培養(yǎng)的MSC分化的影響。 2.測定MSC與BMEC條件培養(yǎng)液中血管內(nèi)皮生長因子(vascular endothelial growth factor,VEGF)和基質(zhì)金屬蛋白酶-9(matrix metalloproteinases-9,MMP-9)含量,觀察缺氧條件下MSC以旁分泌方式對(duì)BMEC增殖、遷移及其單層通透性的影響。 研究方法: 1.分離、培養(yǎng)及鑒定大鼠BMEC和人骨髓MSC:采用兩次酶消化法(0.1%Ⅱ型膠原酶,0.1%膠原酶/分散酶)和密度梯度離心法得到純化的腦微血管片段,加入含10ng/ml bFGF、20%胎牛血清和100μg/ml肝素鈉的DMEM高糖完全培養(yǎng)液,接種于涂布Ⅳ型膠原和纖連蛋白的塑料培養(yǎng)瓶,免疫熒光細(xì)胞化學(xué)法鑒定BMEC的vWF表達(dá);用密度梯度離心法分離人骨髓MSC,采用流式細(xì)胞術(shù)鑒定MSC的CD29、CD34、CD44、CD105和Flk-1表達(dá)。建立缺氧條件下BMEC與MSC直接與間接共培養(yǎng)的模型:缺氧實(shí)驗(yàn)在37℃、93%N2、5%CO_2、2%O_2的缺氧培養(yǎng)箱內(nèi)進(jìn)行;間接共培養(yǎng)使用孔徑0.4μm的Millicell Culture Plate Inserts,BMEC以10%胎牛血清的DMEM低糖(DMEM-10)接種于上層(5×10~3/well),將MSC以DMEM-10接種于下層24孔板內(nèi)(5×10~3/well);直接共培養(yǎng)將兩種細(xì)胞以5000:5000cells/ml的比率混合于DMEM-10后接種于培養(yǎng)瓶或蓋玻片上。觀察缺氧條件下BMEC對(duì)共培養(yǎng)的MSC分化的影響:分別將直接和間接共培養(yǎng)的細(xì)胞在正常和缺氧條件下培養(yǎng)5天,采用流式細(xì)胞術(shù)(定量檢測Flk-1)和免疫熒光細(xì)胞化學(xué)法(定性檢測Flk-1和vWF)對(duì)MSC的分化程度進(jìn)行分析。2.①測定MSC與BMEC條件培養(yǎng)液中VEGF和MMP-9含量:收集正常和缺氧條件下兩種細(xì)胞的條件培養(yǎng)基得到正常的腦微血管內(nèi)皮細(xì)胞條件培養(yǎng)基(BMEC~(CM N))、間充質(zhì)干細(xì)胞條件培養(yǎng)基(MSC~(CM N)),以及缺氧條件下腦微血管內(nèi)皮細(xì)胞條件培養(yǎng)基(BMEC~(CM H))、間充質(zhì)干細(xì)胞條件培養(yǎng)基(MSC~(CM H)),用ELISA檢測各條件培養(yǎng)基中VEGF和MMP-9的含量;②觀察各條件培養(yǎng)基對(duì)BMEC增殖和遷移的影響:使用六種不同培養(yǎng)基(DMEM-10、MSC~(CM N)、MSC~(CM H)、煮沸的MSC~(CM H)培養(yǎng)基、添加抗VEGF抗體和MMP -9抑制劑I的MSC~(CM H)對(duì)BMEC進(jìn)行培養(yǎng),采用Cell Counting Kit-8方法檢測各條件培養(yǎng)基對(duì)BMEC增殖的影響,采用Transwell培養(yǎng)體系檢測各條件培養(yǎng)基對(duì)BMEC遷移的影響;③觀察各條件培養(yǎng)基對(duì)BMEC單層通透性的影響:使用MilliCell-ERS Voltohmmeter測量不同條件培養(yǎng)基(DMEM-10、MSC~(CM N)、MSC~(CM H)、含VEGF抗體的MSC~(CM H)和含MMP-9抑制劑I的MSC~(CM H))對(duì)BMEC單層通透性的影響。 結(jié)果: 1.流式細(xì)胞儀檢測結(jié)果表明MSC呈CD29、CD44、CD105陽性表達(dá),CD34和Flk-1陰性表達(dá);免疫熒光細(xì)胞化學(xué)法檢測BMEC呈vWF陽性表達(dá)。常氧和缺氧條件下的間接和直接共培養(yǎng)的細(xì)胞均能良好生長。常氧條件下間接共培養(yǎng)MSC的Flk-1和vWF蛋白均為陰性表達(dá)。缺氧條件下間接共培養(yǎng)的(7.58±0.58)% (n=6,P=0.034) MSC開始表達(dá)Flk-1蛋白,激光共聚焦顯微鏡也顯示少量細(xì)胞開始出現(xiàn)紅色熒光,但未見綠色熒光的vWF蛋白表達(dá)。正常和缺氧條件下直接共培養(yǎng)5 d時(shí),開始表達(dá)Flk-1蛋白的MSC分別占共培養(yǎng)混合細(xì)胞數(shù)的(13.76±1.67)% (n=6,P0.001)和(23.64±2.50)% (n=6,P0.001),兩者相比有顯著性差異(n=6,P0.001);激光共聚焦也顯示部分MSC開始表達(dá)Flk-1,而在常氧共培養(yǎng)細(xì)胞中未發(fā)現(xiàn)Flk-1陽性的細(xì)胞同時(shí)表達(dá)vWF,值得關(guān)注的是,缺氧直接共培養(yǎng)的混合細(xì)胞中,部分Flk-1陽性細(xì)胞開始同時(shí)表達(dá)vWF的綠色熒光。 2.①ELISA檢測條件培養(yǎng)基中VEGF、MMP-9的含量:缺氧導(dǎo)致BMEC和MSC條件培養(yǎng)基中VEGF含量均明顯增高;MSC~(CM H)中VEGF含量明顯高于BMEC~(CM H);BMEC~(~(CM N))中未檢測到MMP-9,MSC~(CM H)中MMP-9含量明顯高于MSC~(CM N)和BMECCM H。②條件培養(yǎng)基對(duì)BMEC增殖和遷移的影響:與DMEM-10相比,MSC~(CM N)明顯增強(qiáng)了BMEC的增殖,而MSC~(CM H)對(duì)BMEC的增殖作用又明顯強(qiáng)于MSCCM N(0.947±0.103與0.532±0.028,P0.001,n=6);MSC~(CM H)促增殖作用因煮沸而完全喪失,同時(shí)VEGF的阻斷抗體可明顯抑制MSC~(CM H)對(duì)BMEC的增殖作用(0.947±0.103與0.419±0.034,P0.001,n=6),而MMP-9抑制劑對(duì)BMEC的增殖影響不明顯(0.947±0.103與0. 902±0.065,P=0.963,n=6)。與DMEM-10對(duì)照相比,MSC~(CM N)明顯增多了BMEC遷移細(xì)胞的數(shù)量,而MSC~(CM H)對(duì)BMEC的遷移作用又明顯強(qiáng)于MSC~(CM N)(238±27與154±24,P0.01,n=6);VEGF的阻斷抗體可明顯抑制MSC~(CM H)對(duì)BMEC的遷移作用(238±27與150±20,P0.001,n=6),而MMP-9抑制劑對(duì)BMEC的遷移的抑制則更為明顯(238±27與106±18,P0.001,n=6);與對(duì)增殖的影響類似,MSC~(CM H)促遷移作用經(jīng)煮沸處理而完全喪失。③檢測24h內(nèi)不同條件培養(yǎng)基對(duì)內(nèi)皮單層通透性的影響:常氧條件下DMEM-10培養(yǎng)的BMEC電阻值在24 h內(nèi)保持在較穩(wěn)定范圍內(nèi),缺氧狀態(tài)DMEM-10培養(yǎng)BMEC的電阻值在缺氧6~18 h內(nèi)出現(xiàn)明顯下降,約在18 h達(dá)到最低為處理前的(77.2±1.8)%;缺氧狀態(tài)MSC~(CM H)培養(yǎng)的BMEC的電阻值在2 h內(nèi)出現(xiàn)急劇增大,約在2 h達(dá)到最低,為處理前的(50.5±2.6)%,在隨后的2～24 h電阻值略有回升但仍處于較低水平;抗VEGF抗體和MMP-9抑制劑I使MSC~(CM H)培養(yǎng)的BMEC電阻值下降明顯趨緩,最低電阻值分別為處理前的(60.3±3.6)%和(76.0±2.4)%。 結(jié)論: 1.常氧條件下BMEC僅通過旁分泌細(xì)胞因子不足以誘導(dǎo)MSC分化,BMEC能夠通過細(xì)胞直接接觸誘導(dǎo)共培養(yǎng)的MSC向內(nèi)皮分化,缺氧在誘導(dǎo)MSC向內(nèi)皮分化的過程中發(fā)揮重要作用,缺氧條件下,直接共培養(yǎng)的BMEC能誘導(dǎo)更多的MSC更徹底地向內(nèi)皮分化。 2.①M(fèi)SC條件培養(yǎng)基中MMP-9和VEGF的含量均明顯高于BMEC條件培養(yǎng)基,缺氧可介導(dǎo)BMEC和MSC條件培養(yǎng)基中MMP-9和VEGF的含量明顯升高。②MSC可通過旁分泌方式促進(jìn)內(nèi)皮細(xì)胞的增殖和遷移,MMP-9在MSC以旁分泌方式促進(jìn)BMEC遷移過程中發(fā)揮了重要作用,而VEGF則同時(shí)在促進(jìn)BMEC增殖和遷移過程中發(fā)揮重要作用。③MSC可通過旁分泌方式導(dǎo)致BMEC單層通透性的急劇增大,缺氧狀態(tài)下MSC所分泌的大量MMP-9和VEGF是其導(dǎo)致BMEC單層通透性的急劇增大的原因,這是MSC應(yīng)用于缺血性腦血管疾病的治療中值得慎重考慮的問題。
[Abstract]:Research background:
Bone marrow mesenchymal stem cells (mesenchymal stem cells (MSC)) are adult stem cells derived from bone marrow and have multiple potential differentiation. It has proved the ability of MSC to repair and differentiate into a variety of tissues, especially in the repair and reconstruction of blood vessels as a hot point for the treatment of ischemic disease. Brain microvascular endothelial cells (brain microvascular endothel). Ial cells, BMEC) is the most important component of the blood brain barrier, which has the unique physiological characteristics such as close intercellular connection, very few vesicles, and special transmembrane transport system to maintain the ion and metabolic stability of the nerve tissue. In ischemic cerebrovascular disease, the damage of BMEC is caused by the opening of the blood brain barrier and the occurrence of brain edema. The key factors for cell injury in heavy neurons, and the repair and regeneration of the cerebral microvessels in the ischemic penumbra are also the key to save the ischemic neurons. Most studies focus on the repair of damaged nerve tissue in stem cells in the stem cell treatment of ischemic cerebrovascular disease. However, it is damaged by stem cells in the cerebral ischemic areas. The effects of blood brain barrier and microvascular endothelial cells were not deeply studied. In this experiment, the pathological and physiological environment of blood brain barrier and cerebral microvascular in ischemic cerebrovascular disease was simulated under hypoxia conditions, and the effect of BMEC on the differentiation of co cultured MSC, and the proliferation, migration and blood brain barrier model of BMEC by MSC by parathellate secreting methods were observed. The effect of type permeability provides a basic experimental basis for the application of MSC in the treatment of ischemic cerebrovascular diseases.
The purpose of the study:
1. isolation, culture and identification of rat BMEC and human bone marrow MSC, and establish a direct and indirect co culture model of BMEC and MSC under the condition of hypoxia, and observe the effect of BMEC on the direct and indirect co culture of MSC under the condition of hypoxia.
2. the contents of vascular endothelial growth factor (vascular endothelial growth factor, VEGF) and matrix metalloproteinase -9 (matrix metalloproteinases-9, MMP-9) in MSC and BMEC conditioned medium were measured, and the effects of paracrine on proliferation, migration and monolayer permeability under hypoxia were observed.
Research methods:
1. isolation, culture and identification of rat BMEC and human bone marrow MSC: using two enzyme digestion (0.1% type II collagenase, 0.1% collagenase / dispersing enzyme) and density gradient centrifugation to obtain the purified cerebral microvascular fragments, adding DMEM high sugar complete culture solution containing 10ng/ml bFGF, 20% fetal bovine serum and 100 g/ml heparin sodium, inoculated with type IV collagen and fiber. The vWF expression of BMEC was identified by immunofluorescence cytochemical method, and human bone marrow MSC was separated by density gradient centrifugation. The expression of CD29, CD34, CD44, CD105 and Flk-1 in MSC was identified by flow cytometry. The model of BMEC and MSC directly and indirectly cultured under the condition of hypoxia was established: the hypoxia experiment was at 37, and 93%N2,5%CO_2,2%O_2 was missing. In the oxygen incubator, Millicell Culture Plate Inserts with 0.4 m pore diameter was indirectly co cultured, BMEC was inoculated on the upper layer (5 x 10~3/well) with the DMEM low sugar (DMEM-10) of the 10% fetal bovine serum, and MSC was inoculated in the lower layer (5 * 10~3/well) in the lower layer (5 x 10~3/well), and the two kinds of cells were mixed at the ratio after mixing directly. The effects of BMEC on the differentiation of co cultured MSC were observed under the condition of hypoxia: direct and indirect co cultured cells were cultured under normal and anoxic conditions for 5 days respectively. Flow cytometry (quantitative detection of Flk-1) and immunofluorescent cytochemistry (qualitative detection of Flk-1 and vWF) were used to differentiate the degree of differentiation of MSC. Analysis of the content of VEGF and MMP-9 in the conditioned medium of MSC and BMEC: to collect the conditioned medium of normal cerebral microvascular endothelial cells (BMEC~ (CM N)), the conditioned medium of mesenchymal stem cells (MSC~ (CM N)) and the conditioned medium of the cerebral microvascular endothelial cells (BM) under hypoxia conditions (BM), and the conditioned medium of the cerebral microvascular endothelial cells (BM) under hypoxia conditions (BM), and the conditioned medium (BM) (BM) under the condition of hypoxia (BM), and the conditioned medium (BM) (BM) in the condition of hypoxia conditions (BM), and the conditioned medium of the cerebral microvascular endothelial cells (BM) under hypoxia conditions (BM), and the conditioned medium of the cerebral microvascular endothelial cells (BM) under hypoxia conditions (BM), and the condition medium of the cerebral microvascular endothelial cells (BM) under hypoxia conditions (BM), and the condition medium of the cerebral microvascular endothelial cells under the condition of hypoxia (BM) (BM),.2. EC~ (CM H)), the conditioned medium of mesenchymal stem cells (MSC~ (CM H)), the content of VEGF and MMP-9 in the conditioned medium was detected by ELISA. (2) the effects of the culture medium on the proliferation and migration of BMEC were observed. Six different medium (DMEM-10, MSC~), boiling water culture medium were used. The MSC~ (CM H) was used to culture the BMEC, and the Cell Counting Kit-8 method was used to detect the effect of the culture medium on the proliferation of BMEC, and the effect of the culture medium on the BMEC migration was detected by the Transwell culture system. Thirdly, the influence of the medium on the permeability of BMEC monolayer was observed. The effects of DMEM-10 (MSC~, CM N), MSC~ (CM H), MSC~ (CM H) containing VEGF antibody and the inhibitor of the inhibitor containing the inhibitor of VEGF on the permeability of monolayer were studied.
Result:
The results of 1. flow cytometry showed that MSC was CD29, CD44, CD105 positive, CD34 and Flk-1 negative expression, and immunofluorescent cytochemical method was used to detect the positive expression of vWF in BMEC. The indirect and direct co cultured cells under the condition of normoxic and hypoxia could grow well. The Flk-1 and vWF protein of CO cultured MSC under normal oxygen condition were all negative tables. The indirect co culture (7.58 + 0.58)% (n=6, P=0.034) MSC began to express Flk-1 protein in the hypoxic condition. The laser confocal microscope also showed that a small number of cells began to appear red fluorescence, but no green fluorescent vWF protein was expressed. When the normal and hypoxia conditions were directly co cultured 5 D, the MSC that began to express the Flk-1 protein accounted for the co culture mixture respectively. The cell number (13.76 + 1.67)% (n=6, P0.001) and (23.64 + 2.50)% (n=6, P0.001) were significantly different (n=6, P0.001). Laser confocal microscopy also showed that some MSC began to express Flk-1, while no Flk-1 positive cells were found to express vWF in normal oxygen co culture cells. It is worth paying attention to the direct co culture of mixed cells in hypoxia. Some Flk-1 positive cells began to express vWF green fluorescence simultaneously.
2. ELISA detected the content of VEGF, MMP-9 in the conditioned medium: the content of VEGF in the medium of BMEC and MSC was significantly higher than that in the condition medium of BMEC and MSC; the VEGF content in MSC~ (CM H) was obviously higher than BMEC~ (CM). Effect of migration: compared with DMEM-10, MSC~ (CM N) significantly enhanced the proliferation of BMEC, while MSC~ (CM H) significantly increased the proliferation of BMEC than MSCCM N (0.947 + 0.103 and 0.532 + 0.028, P0.001,). 103 and 0.419 + 0.034, P0.001, n=6), and the effect of MMP-9 inhibitors on the proliferation of BMEC was not obvious (0.947 + 0.103 and 0.902 + 0.065, P=0.963, n=6). Compared with DMEM-10, MSC~ (CM N) significantly increased the number of BMEC migration cells, and the migration of MSC~ (238 + 27 and 154 + 0.947); The antibody could obviously inhibit the migration of MSC~ (CM H) to BMEC (238 + 27 and 150 + 20, P0.001, n=6), while the inhibition of MMP-9 inhibitor to BMEC migration was more obvious (238 + 27 and 106 + 18, P0.001, n=6), and similar to the effect on proliferation. MSC~ (CM) promoted the loss of migration through boiling. The effect of the permeability of the skin monolayer: the BMEC resistance value of DMEM-10 culture under the condition of atmospheric oxygen is kept in a relatively stable range within 24 h. The resistance value of the BMEC in the hypoxia state DMEM-10 culture decreases obviously in the anoxic 6~18 h, and the lowest is before the treatment (77.2 + 1.8)%, and the resistance value of the BMEC is 2 within the oxygen deficiency state MSC~ (CM H). There is a sharp increase, at the minimum of about 2 h, for (50.5 + 2.6)% before processing, and a slight increase in the subsequent 2~24 h resistance, but still at a lower level; the resistance to VEGF and MMP-9 inhibitors I makes the BMEC resistance value of MSC~ (CM H) decreased obviously, and the minimum resistance value is divided into (60.3 + 3.6)% and (76 + 2.4)% before treatment.
Conclusion:
1. BMEC can not induce MSC differentiation only through paracrine cytokine, BMEC can induce co cultured MSC to differentiate into endothelium through direct cell contact, and hypoxia plays an important role in inducing MSC to endothelial differentiation, and the direct co cultured BMEC can induce more MSC to differentiate into endothelium more thoroughly under hypoxia conditions.
2. (1) the content of MMP-9 and VEGF in the conditioned medium of MSC was significantly higher than that in the BMEC conditioned medium, and the content of MMP-9 and VEGF in BMEC and MSC conditioned medium was significantly increased by hypoxia. (2) MSC can promote the proliferation and migration of endothelial cells by paracrine mode. MMP-9 plays an important role in promoting BMEC migration in MSC by paracrine mode. In addition, VEGF plays an important role in promoting the proliferation and migration of BMEC. (3) MSC can lead to a sharp increase in the permeability of BMEC monolayer through paracrine mode. A large number of MMP-9 and VEGF secreted by MSC in anoxic state are the cause of the rapid increase in the permeability of BMEC monolayer, which is the treatment of MSC in ischemic cerebrovascular disease. A matter of prudence in the treatment.

【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2008
【分類號(hào)】：R743;R361.2

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10 郭希民 ,王常勇 ,王永紅 ,段翠密 ,趙強(qiáng) ,孫大銘;人骨髓間充質(zhì)干細(xì)胞分離培養(yǎng)及向軟骨細(xì)胞定向分化的實(shí)驗(yàn)研究[J];中華口腔醫(yī)學(xué)雜志;2003年01期

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