本文選題：間充質(zhì)干細(xì)胞 + 視網(wǎng)膜變性��； 參考：《福建醫(yī)科大學(xué)》2015年博士論文

【摘要】：視網(wǎng)膜變性是一類重要的致盲性眼病,可引起視網(wǎng)膜光感受器或神經(jīng)節(jié)細(xì)胞的死亡。當(dāng)前的治療策略側(cè)重于針對病因治療,或通過維持療法延緩視網(wǎng)膜細(xì)胞的死亡過程。隨著對干細(xì)胞研究的深入,骨髓間充質(zhì)干細(xì)胞(bone marrow-derivedmesenchymal stem cells,MSCs)由于其具有可塑性、神經(jīng)保護(hù)、免疫調(diào)控等特性,在治療視網(wǎng)膜疾病方面獲得了越來越多的關(guān)注。而作為視網(wǎng)膜上固有的吞噬細(xì)胞,小膠質(zhì)細(xì)胞在視網(wǎng)膜變性的發(fā)病過程中起到重要作用。MSCs是否與視網(wǎng)膜小膠質(zhì)細(xì)胞相互作用,激活相關(guān)信號通路,維持視網(wǎng)膜自我穩(wěn)定狀態(tài),鮮有相關(guān)文獻(xiàn)報道。趨化因子CX3C模體配體1(Chemokine C-X3-C motif ligand 1,CX3CL1)通過識別其特異性受體CX3CR1,控制著視網(wǎng)膜小膠質(zhì)細(xì)胞的活化程度。本研究通過體外共培養(yǎng)體系,評估CX3CL1基因修飾的MSCs(CX3CL1gene-modified MSCs,CX3CL1-MSCs)對活化的視網(wǎng)膜小膠質(zhì)細(xì)胞功能的影響,并通過體內(nèi)移植觀察其對光損傷視網(wǎng)膜的保護(hù)作用,探討CX3CL1/CX3CR1信號通路的作用。第一部分建立CX3CL1基因修飾的骨髓間充質(zhì)干細(xì)胞目的建立CX3CL1基因修飾的MSCs,并了解其功能。方法全骨髓貼壁法培養(yǎng)SD大鼠MSCs,流式細(xì)胞術(shù)檢測表面標(biāo)記物,并進(jìn)行成骨、成脂分化誘導(dǎo)鑒定,免疫熒光檢測MSCs表達(dá)神經(jīng)營養(yǎng)因子的情況。酶切含有CX3CL1基因的質(zhì)粒與載體質(zhì)粒,線性連接獲得的酶切產(chǎn)物,轉(zhuǎn)化后陽性克隆行PCR鑒定并測序、比對。脂質(zhì)體介導(dǎo)慢病毒三質(zhì)粒共轉(zhuǎn)染293T細(xì)胞,收集上清液,采用離心超濾裝置濃縮,獲得病毒液,Real-time PCR測定病毒滴度。CX3CL1慢病毒感染MSCs,熒光顯微鏡下觀察其感染效率,ELISA檢測細(xì)胞上清中CX3CL1水平,Real-time PCR檢測細(xì)胞CX3CL1 mRNA的表達(dá)情況。結(jié)果全骨髓貼壁法成功分離培養(yǎng)出MSCs,流式細(xì)胞術(shù)檢測第3代的MSCs表面標(biāo)記物的表達(dá)陽性率分別為cd90:(95.21±2.13)%、cd44:(96.75±3.30)%、cd34:(1.84±0.92)%。mscs能夠被誘導(dǎo)分化為成骨細(xì)胞和脂肪細(xì)胞。mscs可在體外表達(dá)cntf、bdnf、gdnf、bfgf。成功構(gòu)建了過表達(dá)cx3cl1基因的慢病毒,滴度至少為2×108tu/ml。cx3cl1慢病毒高效感染mscs,最佳感染復(fù)數(shù)(moi)為10。慢病毒感染mscs后,其cx3cl1的分泌量與cx3cl1mrna的表達(dá)均高于未感染組與空載對照組(f=338.300、640.300,p0.05)。結(jié)論cx3cl1慢病毒感染后,cx3cl1基因能夠整合至mscs基因組中,并準(zhǔn)確轉(zhuǎn)錄,cx3cl1基因修飾的mscs能夠穩(wěn)定表達(dá)和分泌cx3cl1。第二部分cx3cl1基因修飾的骨髓間充質(zhì)干細(xì)胞對活化的視網(wǎng)膜小膠質(zhì)細(xì)胞生物學(xué)功能的影響目的評估cx3cl1/cx3cr1信號通路在mscs和視網(wǎng)膜小膠質(zhì)細(xì)胞相互作用中的影響。方法采用視網(wǎng)膜膠質(zhì)細(xì)胞混合培養(yǎng)和振蕩分離的方法分離培養(yǎng)sd大鼠視網(wǎng)膜小膠質(zhì)細(xì)胞,免疫熒光染色鑒定細(xì)胞純度。脂多糖(lps)刺激視網(wǎng)膜小膠質(zhì)細(xì)胞,并與mscs、cx3cl1基因修飾的mscs(cx3cl1-mscs)、中和性抗體封閉cx3cl1的mscs共培養(yǎng)24h,觀察共培養(yǎng)后視網(wǎng)膜小膠質(zhì)細(xì)胞增殖、吞噬、遷移能力的變化,griess法檢測其一氧化氮(no)釋放量,采用real-timepcr、westernblot、elisa等方法分析其表達(dá)和分泌細(xì)胞因子的變化。結(jié)果視網(wǎng)膜膠質(zhì)細(xì)胞混合培養(yǎng)和振蕩分離的方法成功分離培養(yǎng)出視網(wǎng)膜小膠質(zhì)細(xì)胞,免疫熒光檢測顯示,cd11b、iba1陽性率分別為(96.18±3.40)%、(94.05±4.18)%,gs呈陰性表達(dá),說明獲得的視網(wǎng)膜小膠質(zhì)細(xì)胞純度較高。lps能夠活化視網(wǎng)膜小膠質(zhì)細(xì)胞。與mscs共培養(yǎng),使活化的視網(wǎng)膜小膠質(zhì)細(xì)胞的增殖被抑制(f=32.280,p0.05),而吞噬、遷移能力增強(f=72.200、20.020,p0.05),tnf-α、il-1β、inosmrna表達(dá)下調(diào)(f=20.710、63.530、78.580,p0.05),cntf、bdnf、cx3cr1mrna表達(dá)量上調(diào)(f=169.400、29.050、79.060,p0.05),bdnf、cntf蛋白表達(dá)量增加(f=24.460、20.510,p0.05),細(xì)胞上清中no、tnf-α、il-1β分泌量降低(f=23.670、84.960、30.760,p0.05)。與cx3cl1-mscs共培養(yǎng),能夠增強這些反應(yīng),而與cx3cl1封閉的mscs共培養(yǎng),能夠抑制這些反應(yīng)。結(jié)論MSCs可能主要通過CX3CL1/CX3CR1信號通路維持視網(wǎng)膜小膠質(zhì)細(xì)胞的穩(wěn)態(tài)。第三部分視網(wǎng)膜下腔移植CX3CL1基因修飾的骨髓間充質(zhì)干細(xì)胞對光損傷視網(wǎng)膜的保護(hù)作用觀察目的探討視網(wǎng)膜下腔移植CX3CL1基因修飾的MSCs(CX3CL1-MSCs)對光損傷視網(wǎng)膜結(jié)構(gòu)和功能的保護(hù)作用。方法SD大鼠散瞳后持續(xù)暴露于(9500±500)Lux的白光24h。HE染色觀察強光暴露對視網(wǎng)膜組織結(jié)構(gòu)的影響,末端脫氧核苷酸轉(zhuǎn)移酶介導(dǎo)的dUTP缺口末端標(biāo)記(TUNEL)測定法檢測視網(wǎng)膜細(xì)胞凋亡情況。將MSCs和CX3CL1-MSCs移植到光損傷大鼠視網(wǎng)膜下腔,比較其向視網(wǎng)膜內(nèi)層遷移的能力,采用HE染色觀察外核層厚度變化,閃光視網(wǎng)膜電圖(F-ERG)和TUNEL法評估其對宿主視網(wǎng)膜的保護(hù)作用。ED-1抗體標(biāo)記視網(wǎng)膜上活化的小膠質(zhì)細(xì)胞。Western blot檢測移植后宿主視網(wǎng)膜表達(dá)CNTF、BDNF、IL-1β、TNF-α的水平。免疫熒光定位視網(wǎng)膜上CNTF、BDNF的表達(dá)。結(jié)果光損傷后視網(wǎng)膜外核層厚度較正常組變薄,凋亡細(xì)胞增多(t=8.009、8.753,P0.05)。視網(wǎng)膜下腔移植后,CX3CL1-MSCs向視網(wǎng)膜內(nèi)層的遷移能力強于MSCs(t=3.674,P0.05)。與MSCs移植組、DMEM移植組相比,移植CX3CL1-MSCs對于延緩視網(wǎng)膜外核層變薄,抑制視網(wǎng)膜細(xì)胞凋亡,減少活化的視網(wǎng)膜小膠質(zhì)細(xì)胞的數(shù)量,具有更好地作用。同時,F-ERG結(jié)果顯示移植后1w、3w、6w,移植CX3CL1-MSCs能夠更好地保護(hù)視網(wǎng)膜功能。移植后3w,CX3CL1-MSCs移植組視網(wǎng)膜CNTF、BDNF的蛋白表達(dá)量高于MSCs移植組和DMEM移植組(FCNTF=31.490,FBDNF=26.040,P0.05),而IL-1β、TNF-α的蛋白表達(dá)量低于其他組(FIL-1β=62.730,FTNF-α=21.940,P0.05)。免疫熒光顯示,CX3CL1-MSCs移植后CNTF、BDNF能夠表達(dá)于視網(wǎng)膜全層和整合入視網(wǎng)膜的MSCs。結(jié)論視網(wǎng)膜下腔移植CX3CL1-MSCs可強化對光損傷視網(wǎng)膜結(jié)構(gòu)和功能的保護(hù)作用。
[Abstract]:Retinal degeneration is an important type of blindness, which can cause the death of retinal photoreceptors or ganglion cells. The current treatment strategy focuses on etiological treatment, or delays the death process of retinal cells through maintenance therapy. With the further study of stem cells, bone marrow mesenchymal stem cells (bone marrow-derivedmesench) Ymal stem cells, MSCs) has gained more and more attention in the treatment of retinal diseases because of its plasticity, neuroprotection, immune regulation and so on. As an inherent phagocyte on the retina, microglia plays an important role in the pathogenesis of retinal degeneration, whether.MSCs is associated with retinal microglia. Function, activating the related signaling pathway to maintain the self stable state of the retina, rarely reported in the literature. Chemokine ligand 1 (Chemokine C-X3-C motif ligand 1, CX3CL1) controls the degree of activation of retinal microglia by identifying its specific receptor CX3CR1. This study evaluated CX3CL1 based in vitro co culture system. The effect of modified MSCs (CX3CL1gene-modified MSCs, CX3CL1-MSCs) on the function of activated retinal microglia, and to observe the protection of light damaged retina by transplantation in vivo, and explore the role of CX3CL1/CX3CR1 signaling pathway. The first part established the CX3CL1 gene modified bone marrow mesenchymal stem cells for the purpose of establishing the CX3CL1 base. Because of the modified MSCs, and understand its function. Methods all bone marrow adherent method was used to train SD rat MSCs, flow cytometry was used to detect surface markers, osteogenesis, differentiation induction and identification of lipid differentiation, immunofluorescence detection of MSCs expression of neurotrophic factor. The enzyme cut products containing CX3CL1 gene particles and carrier plasmid, linear connection obtained enzyme cut products, turn The positive clones were identified and sequenced by PCR. Compared with the liposome mediated lentivirus three plasmids, 293T cells were co transfected, the supernatant was collected and concentrated by the centrifuge ultrafiltration device to obtain the virus. Real-time PCR was used to determine the virus titer.CX3CL1 lentivirus infection MSCs. The infection efficiency was observed under the fluorescence microscope. The CX3CL1 level in the cell supernatant was detected by ELISA. The level of CX3CL1 was detected by ELISA Real-time PCR was used to detect the expression of CX3CL1 mRNA in cells. Results all bone marrow adherent methods were successfully isolated and cultured for MSCs. The positive rates of MSCs surface markers in third generation by flow cytometry were cd90: (95.21 + 2.13)%, cd44: (96.75 + 3.30)% and cd34: (1.84 + 0.92)%.mscs can be induced into osteoblasts and fatty cells.Mscs In vitro expression of CNTF, BDNF, GDNF, bfgf. successfully constructed the lentivirus that overexpressed cx3cl1 gene, and the titer was at least 2 * 108tu/ml.cx3cl1 lentivirus infection MSCs, and the optimal infection complex number (MOI) was 10. lentivirus infection MSCs, and the secretion of cx3cl1 and cx3cl1mrna were higher than those in the uninfected and no-load control group (f=338.300640.300, P0.05) conclusion after cx3cl1 lentivirus infection, the cx3cl1 gene can be integrated into the MSCs genome and transcribed accurately. The cx3cl1 gene modified MSCs can express and secrete the cx3cl1. second partial cx3cl1 gene modified mesenchymal stem cells on the activated retinal microglia biological function in order to evaluate the purpose of evaluating cx3cl1/cx3cr1. The effect of signal pathway on the interaction of MSCs and retinal microglia. Methods the microglia of SD rat retinal microglia were isolated and cultured by mixed culture of glial cells and oscillatory separation, and the purity of the cells was identified by immunofluorescence staining. LPS stimulated the microglia in the retina membrane and modified with the MSCs, cx3cl1 gene. MSCs (cx3cl1-mscs), neutralizing antibody closed cx3cl1 MSCs co culture 24h, observed the proliferation, phagocytosis and migration of retinal microglia after co culture. Griess method was used to detect the release of nitric oxide (no). The changes of expression and secretion of cytokines were analyzed by real-timepcr, Westernblot, ELISA, etc. results of retinal glia. The retinal microglia cells were successfully isolated and cultured by mixed culture and oscillatory separation. The immunofluorescence detection showed that the positive rates of CD11b, Iba1 were (96.18 + 3.40)%, (94.05 + 4.18)% and GS negative expression, indicating that the obtained retinal microglia with high purity.Lps could activate retinal microglia. Co culture with MSCs, The proliferation of activated retinal microglia was inhibited (f=32.280, P0.05), and phagocytosis, mobility enhancement (f=72.200,20.020, P0.05), tnf- alpha, IL-1 beta, iNOSmRNA expression downregulation (f=20.710,63.530,78.580, P0.05), CNTF, BDNF, cx3cr1mrna expression increased 10, P0.05), the secretion of no, tnf- a, and IL-1 beta in the cell supernatant decreased (f=23.670,84.960,30.760, P0.05). Co culture with cx3cl1-mscs can enhance these reactions, and can inhibit these reactions with cx3cl1 closed MSCs co culture. Conclusion MSCs may maintain the homeostasis of retinal microglia mainly through CX3CL1/ CX3CR1 signal pathway. Third parts can be maintained by CX3CL1/ CX3CR1 signal pathway. Protective effect of bone marrow mesenchymal stem cells modified by CX3CL1 gene on light damage retina by subretinal transplantation to investigate the protective effect of CX3CL1 gene modified MSCs (CX3CL1-MSCs) on retinal structure and function of light damaged retina transplantation. Methods SD rats were exposed to white light 24h. (9500 + 500) Lux after diffuse pupil of SD rats. The effect of strong light exposure on retinal tissue structure was observed by HE staining. Apoptosis of retinal cells was detected by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay. MSCs and CX3CL1-MSCs were transplanted into the inferior retinal cavity of rats with light damage, and the ability to migrate to the inner layer of the retina was compared. HE staining was used to observe the outer layer of retina. Nuclear layer thickness change, flash electroretinogram (F-ERG) and TUNEL method to evaluate the protection of the retina,.ED-1 antibody labeled retinal activation microglia.Western blot was used to detect the expression of CNTF, BDNF, IL-1 beta, TNF- alpha in the host retina after transplantation. The immunofluorescent localization of CNTF, BDNF on the retina. Results light damage The thickness of the outer retinal nucleus was thinner and apoptotic cells increased (t=8.009,8.753, P0.05). After the subretinal transplantation, the migration of CX3CL1-MSCs to the inner retina was stronger than MSCs (t=3.674, P0.05). Compared with the MSCs transplantation group and DMEM transplantation group, the transplantation CX3CL1-MSCs was used to delay the thinning of the outer retinal nuclei and inhibit the apoptosis of the retina cells. To reduce the number of activated retinal microglia, it has a better effect. At the same time, F-ERG results show that 1W, 3W, 6W, and transplanted CX3CL1-MSCs can better protect the retinal function. 3W, CX3CL1-MSCs transplantation group after transplantation, the retinal CNTF, the protein expression of BDNF is higher than that of the MSCs transplantation group and the DMEM transplantation group. 0.05), while the protein expression of IL-1 beta, TNF- alpha was lower than that of other groups (FIL-1 beta =62.730, FTNF- alpha =21.940, P0.05). Immunofluorescence showed that after CX3CL1-MSCs transplantation CNTF, BDNF could be expressed in the whole retina and integrated into the retina, and the MSCs. conclusion retina transplantation CX3CL1-MSCs could strengthen the protection of the structure and function of light damaged retina.

【學(xué)位授予單位】：福建醫(yī)科大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R774.1

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