【摘要】：一系列累及視網(wǎng)膜的疾病都會造成視網(wǎng)膜感光細(xì)胞和其他視網(wǎng)膜神經(jīng)元的丟失,這些疾病包括遺傳性疾病,比如視網(wǎng)膜色素變性；還包括許多發(fā)病率更高的疾病,比如黃斑變性、視網(wǎng)膜脫離、青光眼、糖尿病視網(wǎng)膜病變等等。由于視網(wǎng)膜同顱內(nèi)的腦神經(jīng)組織一樣,缺乏有效的自我修復(fù)機能,所以以上這些疾病通常都會造成患者視力不可逆性的喪失。臨床上對這些疾病造成的視力損傷多是采用支持保護(hù)性治療,真正能挽救和恢復(fù)的視力有限。這些疾病造成視力損傷的根本原因是視網(wǎng)膜功能細(xì)胞的死亡、減少,所以對這類細(xì)胞的替換或再生治療是有希望治愈疾病并恢復(fù)視力的有效手段。 近年的研究熱點之一是,通過手術(shù)注射的方式將視網(wǎng)膜祖細(xì)胞或前體細(xì)胞移植入病變的視網(wǎng)膜下。有對動物疾病模型的研究表明,注入受體視網(wǎng)膜下的細(xì)胞可以向受體視網(wǎng)膜移行,并能夠表達(dá)某些成熟視網(wǎng)膜細(xì)胞的蛋白標(biāo)志,且能夠檢測到視網(wǎng)膜功能的改善。所以細(xì)胞移植治療視網(wǎng)膜變性性疾病是一種可行的、有希望的治療手段。如何通過體外培養(yǎng)的方式,擴增得到大量的可供于研究及移植治療的細(xì)胞,是研究者需要解決的一個問題。而作為細(xì)胞移植受體的疾病動物模型,對于我們深入理解這類疾病有著重要意義；觀察并了解動物模型疾病的發(fā)生、發(fā)展過程及其中形態(tài)和功能的變化,是十分必要的。這樣,我們不僅對疾病過程中各方面的改變建立了一個基線標(biāo)準(zhǔn),同時也使得對后續(xù)的干預(yù)治療的效果進(jìn)行觀察和評估成為可能。 本研究將通過三部分,來介紹人類視網(wǎng)膜祖細(xì)胞(human retinal progenitor cell, hRPC)移植入視網(wǎng)膜變性小鼠的相關(guān)研究。第一部分：人類視網(wǎng)膜祖細(xì)胞的體外培養(yǎng)；第二部分：對于rhodopsin-/-小鼠視網(wǎng)膜變性過程的動態(tài)連續(xù)觀察；第三部分：rhodopsin-/-小鼠視網(wǎng)膜下hRPC移植后的視網(wǎng)膜形態(tài)和功能變化的動態(tài)觀察。 第一部分：人類視網(wǎng)膜祖細(xì)胞的低氧培養(yǎng) 目的：比較人類視網(wǎng)膜祖細(xì)胞(hRPC)在常氧濃度培養(yǎng)(20%氧濃度)和低氧濃度培養(yǎng)(3%氧濃度)下各方面性狀的差異,如細(xì)胞的自我更新、增殖及細(xì)胞向視網(wǎng)膜細(xì)胞分化的能力等。初步研究相關(guān)的細(xì)胞因子及信號通路,了解相關(guān)現(xiàn)象發(fā)生的機制。 方法：從人類胎兒視網(wǎng)膜中分離得到視網(wǎng)膜祖細(xì)胞,進(jìn)行體外培養(yǎng)。培養(yǎng)條件分為常氧培養(yǎng)(20%氧濃度)和低氧培養(yǎng)(3%氧濃度),觀察細(xì)胞在兩種培養(yǎng)條件下生物學(xué)特性的差異,并在特定時間點收集各組細(xì)胞進(jìn)行相關(guān)細(xì)胞因子的蛋白表達(dá)水平檢測(蛋白免疫印跡實驗、免疫細(xì)胞化學(xué)檢測)和基因mRNA水平檢測(聚合酶鏈?zhǔn)椒磻?yīng)),通過這些檢測的結(jié)果推斷各細(xì)胞因子(低氧誘導(dǎo)因子)在低氧培養(yǎng)中發(fā)揮的作用。 結(jié)果：hRPC在低氧培養(yǎng)(3%氧濃度)條件下細(xì)胞增殖曲線及MTT實驗均提示較好的細(xì)胞增殖水平,實時熒光定量PCR和細(xì)胞免疫化學(xué)染色也分別從相關(guān)基因mRNA水平及蛋白表達(dá)水平方而說明了細(xì)胞增殖水平的增強,如Ki67、CyclinD1。而且低氧培養(yǎng)條件下的hRPC維持了向視網(wǎng)膜細(xì)胞分化的能力,Klf4、c-Myc在基因和蛋白水平表達(dá)均高于常氧培養(yǎng)條件。低氧誘導(dǎo)因子la(Hypoxia inducible factor-1a, HIF-1a)在低氧培養(yǎng)的細(xì)胞中表達(dá)高于常氧培養(yǎng),且表達(dá)水平隨時間而變化。 結(jié)論：本研究證明低氧濃度培養(yǎng)環(huán)境有利于人類視網(wǎng)膜祖細(xì)胞的體外擴增,并能夠維持細(xì)胞向視網(wǎng)膜細(xì)胞分化的能力。低氧誘導(dǎo)因子1a可能在其中發(fā)揮關(guān)鍵作用。低氧培養(yǎng)模式可以為視網(wǎng)膜變性性疾病的研究和今后可能的細(xì)胞移植治療提供大量未分化狀態(tài)的人類視網(wǎng)膜祖細(xì)胞。 第二部分：Rhodopsin-/-鼠視網(wǎng)膜變性過程的在體動態(tài)觀察 目的：視網(wǎng)膜色素變性(RP)和老年性黃斑變性(AMD)是兩類主要的造成不可逆性失明的視網(wǎng)膜變性性疾病。嚙齒類動物模型是我們理解這類疾病的重要工具。之前的研究已經(jīng)表明視網(wǎng)膜紫質(zhì)是視網(wǎng)膜光傳導(dǎo)過程中必不可少的要素,同時也是視桿細(xì)胞外節(jié)重要的結(jié)構(gòu)蛋白。Rhodopsin-/-鼠不表達(dá)視網(wǎng)膜紫質(zhì),不形成視桿細(xì)胞外節(jié),在出生后短短的幾個月內(nèi)視桿細(xì)胞便會消失,繼之是視錐細(xì)胞功能和數(shù)量的喪失。本部分研究采用頻域光學(xué)相干斷層掃描(Spectral Domain Optical Coherence Tomography, SD-OCT)動態(tài)連續(xù)性觀察rhodopsin-/鼠視網(wǎng)膜形態(tài)方面的變化。 方法：選擇出生后第3、6、9和12周的rhodopsin-/鼠(C57B16rhodopsin基因敲除)和野生型C57B16鼠用于本研究。SD-OCT采用放射狀體積掃描模式(以視盤為中心,直徑1.3mm的掃描范圍)。每個體積掃描包含100個B掃描(每個B掃描包含1000個A掃描)。選取特定的掃描進(jìn)行視網(wǎng)膜外核層(outer nuclear layer,ONL)厚度的測量。在相應(yīng)的時間點進(jìn)行視網(wǎng)膜組織學(xué)檢查,并將得到的數(shù)據(jù)和SD-OCT所獲得的數(shù)據(jù)進(jìn)行比較。記錄暗適應(yīng)和明適應(yīng)條件下的視網(wǎng)膜電圖(Electroretinograms, ERG),對視網(wǎng)膜功能學(xué)變化和形態(tài)學(xué)變化進(jìn)行相關(guān)性分析。 結(jié)果：SD-OCT測量數(shù)據(jù)顯示rhodopsin-/-鼠視網(wǎng)膜外核層厚度在其出生后第3周至第12周逐漸變薄。第3、6、9和12周的厚度值分別為40.6±1.61μm,27.9±1.65μm,14.5±0.7μm和6.0±0.78μm。在rhodopsin-/鼠視網(wǎng)膜無法觀察到視桿細(xì)胞外節(jié)。視網(wǎng)膜組織學(xué)檢測數(shù)據(jù)顯示出同OCT檢測相同的趨勢。在第3周時,rhodopsin-/鼠視網(wǎng)膜外核層有9-10層細(xì)胞核,而C57B16鼠有11-12層細(xì)胞核；到第12周時,rhodopsin-/-鼠外核層細(xì)胞核層數(shù)已經(jīng)減低到1-2層,而野生型小鼠細(xì)胞核層數(shù)穩(wěn)定在11-12層。Rhodopsin-/鼠的明適應(yīng)和暗適應(yīng)條件下的ERG均不能見到明顯a波,而b波波幅也隨年齡增長而降低,同形態(tài)學(xué)觀察到的結(jié)果一致。而野生型C57B16鼠在各時間點形態(tài)學(xué)和功能學(xué)的測量值基本穩(wěn)定。 結(jié)論：通過SD-OCT測量得到的數(shù)據(jù)確認(rèn)了rhodopsin-/鼠外核層厚度在其出生后逐漸變薄,而在野生型小鼠中則沒有發(fā)現(xiàn)變化。并且視網(wǎng)膜組織學(xué)檢測和ERG功能學(xué)的定量檢測都證實了OCT所得到的結(jié)果。因此,SD-OCT可以作為一種無創(chuàng)性的、有效并且可靠的研究工具,用于動態(tài)觀察視網(wǎng)膜變性性疾病動物模型的疾病變化過程。 第三部分：Rhodopsin-/-鼠視網(wǎng)膜下視網(wǎng)膜祖細(xì)胞的移植 目的：將體外培養(yǎng)擴增的人視網(wǎng)膜祖細(xì)胞通過手術(shù)方式注入藥物(環(huán)孢素)免疫抑制的rhodopsin-/-鼠視網(wǎng)膜下,觀察細(xì)胞移植后的存活、移行、和受體視網(wǎng)膜結(jié)合及分化等情況,評估移植后視網(wǎng)膜變性小鼠的視網(wǎng)膜形態(tài)(組織學(xué)檢測和SD-OCT檢測)和功能(ERG)的相關(guān)變化。 方法：移植細(xì)胞為體外低氧濃度(3%)培養(yǎng)的hRPC(細(xì)胞代數(shù)為第7至第9代)。移植受體鼠rhodopsin-/-鼠經(jīng)過環(huán)孢素免疫抑制。通過手術(shù)方式,將hRPC(對照組注入PBS)注射入小鼠視網(wǎng)膜下。于術(shù)后第3天和第3周對術(shù)眼進(jìn)行OCT觀察,并于第3周OCT觀察結(jié)束后進(jìn)行ERG檢測,隨后處死小鼠進(jìn)行視網(wǎng)膜組織學(xué)檢測。 結(jié)果：在移植之后的第3天和第3周分別進(jìn)行OCT觀察,均可在移植成功的小鼠視網(wǎng)膜下見到移植細(xì)胞存在,并能夠通過隨后的組織學(xué)檢查證實。對組織學(xué)切片進(jìn)行相關(guān)免疫染色后可以觀察到rhodopsin-/鼠視網(wǎng)膜下存活的移植細(xì)胞,但是在移植后第3周也幾乎觀察不到hRPC向受體鼠視網(wǎng)膜的移行和整合。在對移植細(xì)胞小鼠和對照小鼠(僅在視網(wǎng)膜下注入PBS)的視網(wǎng)膜功能學(xué)檢查(ERG)中未見明顯差異。 結(jié)論：通過環(huán)孢素對細(xì)胞移植受體鼠進(jìn)行免疫抑制,可以提高移植細(xì)胞的存活率。移植后細(xì)胞并未向受體視網(wǎng)膜移行和整合,視網(wǎng)膜功能檢測未見改善。 一、主要研究結(jié)果 1.人類視網(wǎng)膜祖細(xì)胞在低氧濃度培養(yǎng)條件下表現(xiàn)出較好的增殖趨勢,增殖相關(guān)因子Ki67、Cyclin D1在基因和蛋白水平的表達(dá)也高于常氧培養(yǎng)；而低氧條件下干細(xì)胞特性相關(guān)因子c-Myc、Klf4也同樣有較高的基因和蛋白表達(dá)水平。低氧誘導(dǎo)因子1a在低氧培養(yǎng)的細(xì)胞中有表達(dá),而在常氧培養(yǎng)細(xì)胞中僅有低量表達(dá)。 2. SD-OCT測量數(shù)據(jù)顯示rhodopsin-/-鼠視網(wǎng)膜外核層厚度在其出生后第3周至第12周逐漸變薄。視網(wǎng)膜組織學(xué)檢測也顯示出相同的趨勢。Rhodopsin-/-鼠的ERG不能見到明顯a波,而b波波幅也隨年齡增長而降低,同形態(tài)學(xué)觀察到的結(jié)果一致。而野生型C57B16鼠在各時間點形態(tài)學(xué)和功能學(xué)的測量值基本穩(wěn)定。 3. SD-OCT可在移植成功的小鼠視網(wǎng)膜下見到移植細(xì)胞存在,并能夠通過隨后的組織學(xué)檢查證實。組織學(xué)切片可以觀察到rhodopsin-/鼠視網(wǎng)膜下存活的移植細(xì)胞,但幾乎觀察不到細(xì)胞向受體鼠視網(wǎng)膜的移行和整合。在對移植細(xì)胞小鼠和對照小鼠(視網(wǎng)膜下注入PBS)的視網(wǎng)膜功能學(xué)檢查(ERG)中未見明顯差異。 二、研究結(jié)論 1.低氧濃度培養(yǎng)條件有利于人類視網(wǎng)膜祖細(xì)胞的體外擴增,并能夠維持細(xì)胞的分化能力。低氧培養(yǎng)條件下,細(xì)胞所表現(xiàn)出來的性狀可能受到低氧誘導(dǎo)因子1a的調(diào)控。低氧濃度培養(yǎng)可作為人類視網(wǎng)膜祖細(xì)胞常規(guī)的培養(yǎng)方式。 2.通過SD-OCT測量得到的數(shù)據(jù)確認(rèn)了rhodopsin-/鼠外核層厚度在其出生后逐漸變薄。并且視網(wǎng)膜組織學(xué)檢測和ERG功能學(xué)的定量檢測都證實了OCT所得到的結(jié)果。SD-OCT可以作為一種無創(chuàng)性的、有效并且可靠的研究工具,用于動態(tài)觀察視網(wǎng)膜變性性疾病動物模型的疾病變化過程。 3.通過環(huán)孢素對rhodopsin-/鼠進(jìn)行免疫抑制,可以提高移植細(xì)胞的存活,但移植后細(xì)胞在觀察時間內(nèi)并未向受體視網(wǎng)膜移行和整合。細(xì)胞移植后未見視網(wǎng)膜功能的改善。
[Abstract]:A series of diseases involving the retina can cause the loss of photoreceptors and other retinal neurons. These diseases include hereditary diseases, such as retinitis pigmentosa, and many more common diseases, such as macular degeneration, retinal detachment, glaucoma, diabetic retinopathy and so on. These diseases usually result in irreversible loss of vision. Clinically, most of the visual impairment caused by these diseases is caused by supportive protective treatment, which can really save and restore limited vision. This is due to the death and decrease of retinal functional cells, so replacement or regeneration of these cells is an effective means of hopefully curing the disease and restoring vision.
In recent years, one of the research hotspots is the transplantation of retinal progenitor cells or precursor cells into the diseased retina by surgical injection. Studies on animal disease models have shown that cells injected into the recipient retina can migrate to the recipient retina, and can express some protein markers of mature retinal cells, and can be detected. So cell transplantation is a feasible and promising treatment for retinal degenerative diseases. How to amplify a large number of cells for research and transplantation through in vitro culture is a problem that researchers need to solve. Animal models are of great importance to our understanding of these diseases; it is necessary to observe and understand the occurrence, development and morphological and functional changes of animal models. Thus, we not only establish a baseline standard for changes in various aspects of the disease process, but also make follow-up interventions and treatments possible. It is possible to observe and evaluate the effect.
In this study, three parts will be introduced to study the transplantation of human retinal progenitor cell (hRPC) into mice with retinal degeneration. The dynamic changes of retinal morphology and function after subretinal hRPC transplantation in rhodopsin-/- mice.
Part one: hypoxic culture of human retinal progenitor cells
AIM: To compare the characteristics of human retinal progenitor cells (hRPC) cultured in normoxia (20% oxygen concentration) and hypoxia (3% oxygen concentration), such as cell self-renewal, proliferation and differentiation to retinal cells. System.
METHODS: Retinal progenitor cells were isolated from human fetal retina and cultured in vitro. The culture conditions were divided into normoxic culture (20% oxygen concentration) and hypoxic culture (3% oxygen concentration). The differences of biological characteristics between the two cultures were observed and the expression of related cytokines in the cells was collected at a specific time point. Level detection (protein immunoblotting, immunocytochemical detection) and gene mRNA level detection (polymerase chain reaction) were used to infer the role of cytokines (hypoxia inducible factors) in hypoxia culture.
Results: The proliferation curve and MTT assay of hRPC in hypoxic culture (3% oxygen concentration) showed a good level of cell proliferation. Real-time fluorescence quantitative PCR and immunocytochemical staining also showed the enhancement of cell proliferation from the mRNA level and protein expression level of related genes, such as Ki67 and Cyclin D1. Hypoxia inducible factor-1a (HIF-1a) expression was higher in hypoxia-cultured cells than in normoxia-cultured cells, and the expression level of Klf4 and c-Myc changed with time.
CONCLUSION: This study demonstrates that hypoxia culture environment is conducive to the expansion of human retinal progenitor cells in vitro and can maintain the ability of cells to differentiate into retinal cells. Treatment provides a large number of undifferentiated human retinal progenitor cells.
The second part: in vivo dynamic observation of retinal degeneration in Rhodopsin-/- rats.
OBJECTIVE: Retinal pigment degeneration (RP) and age-related macular degeneration (AMD) are two major types of irreversible blindness-causing retinal degenerative diseases. Rodent animal models are an important tool for understanding these diseases. Previous studies have shown that retinal purple is an essential element in retinal light transmission, and at the same time Rhodopsin - / - mice do not express retinal purple, do not form rod extracellular segments, rod cells disappear within a few months after birth, followed by loss of cone cell function and number. Ence Tomography (SD-OCT) was used to observe the morphological changes of retina in rhodopsin-/ rats.
METHODS: Rhodopsin - / mouse (C57B16 rhodopsin knockout) and wild-type C57B16 mice at 3, 6, 9 and 12 weeks after birth were selected for this study. SD-OCT was performed in a radiovolume scan mode (with an optic disc as the center and a scan range of 1.3 mm in diameter). Each volume scan consisted of 100 B scans (each B scan consisted of 1,000 A scans). The thickness of the outer nuclear layer (ONL) was measured by scanning. Retinal histology was performed at the corresponding time points, and the data were compared with those obtained by SD-OCT. Electroretinograms (ERG) were recorded under dark and light adaptation conditions, and the changes of retinal function and shape were observed. Correlation analysis of state changes.
Results: SD-OCT measurements showed that the thickness of rhodopsin-/-rat retinal outer nuclear layer gradually thinned from the 3rd week to the 12th week after birth. The thickness values at the 3rd, 6th, 9th and 12th weeks were 40.6 (+ 1.61), 27.9 (+ 1.65), 14.5 (+ 0.7) and 6.0 (+ 0.78) microns, respectively. At week 3, there were 9-10 layers of nuclei in the rhodopsin-/ mouse extraretinal nucleus layer, and 11-12 layers in the C57B16 mouse. By week 12, the number of nuclei in the rhodopsin-/-mouse outer nucleus layer had been reduced to 1-2 layers, while the number of nuclei in the wild type mice was stable at 11-12 layers. The ERG under dark adaptation could not see a wave, but the amplitude of B wave decreased with age, which was consistent with the morphological observation. The morphological and functional measurements of wild type C57B16 mice were basically stable at all time points.
CONCLUSIONS: Data from SD-OCT measurements confirm that rhodopsin-/mouse outer nuclear layer thickness gradually thinned after birth, but no change was found in wild-type mice. The results of OCT were confirmed by histological examination and quantitative detection of ERG function. Therefore, SD-OCT can be used as a noninvasive and effective method. And a reliable research tool can be used to dynamically observe the changes of retinal degenerative diseases in animal models.
The third part: transplantation of retinal progenitor cells from Rhodopsin-/- mice.
OBJECTIVE: To observe the survival, migration, and retinal binding and differentiation of human retinal progenitor cells (RPCs) after transplantation into rhodopsin - / - mice subretina, which is immunosuppressed by cyclosporine, and to evaluate the retinal morphology (histological examination and SD-OCT) of retinal degeneration mice after transplantation. Correlation between detection and function (ERG).
METHODS: The transplanted cells were cultured in vitro with hypoxia (3%) for 7 to 9 generations. The recipient rhodopsin - / - mice were subjected to cyclosporine immunosuppression. The hRPC (control group injected PBS) was injected into the retina of the mice by operation. OCT was observed on the 3rd day and 3rd week after operation, and OCT was observed on the 3rd week after operation. After ERG, the mice were sacrificed for histological examination of the retina.
RESULTS: OCT observation on the 3rd day and the 3rd week after transplantation showed that transplanted cells were present in the subretinal region of the transplanted mice and could be confirmed by subsequent histological examination. The migration and integration of hRPC into the retina of recipient mice were almost not observed at the 3rd week after transplantation. There was no significant difference in the retinal function test (ERG) between transplanted cell mice and control mice (only PBS was injected into the retina).
CONCLUSION: Cyclosporin can improve the survival rate of transplanted cells by immunosuppression in recipient mice. The transplanted cells did not migrate and integrate to the recipient retina, and the retinal function was not improved.
I. main findings
1. Human retinal progenitor cells showed a good proliferation trend under hypoxic conditions, and the expression of proliferation-related factors Ki67 and Cyclin D1 were also higher than those in normoxic conditions. The expression levels of stem cell characteristic-related factors c-Myc and Klf4 were also higher under hypoxic conditions. A was expressed in hypoxic culture cells but only in low oxygen cultured cells.
2. SD-OCT measurements showed that the thickness of the outer retinal nucleus of rhodopsin-/-mice gradually thinned from the 3rd week to the 12th week after birth. Retinal histological examination also showed the same trend. ERG of Rhodopsin-/-mice could not see obvious a wave, but the amplitude of B wave decreased with age, which was consistent with morphological observation. The morphological and functional measurements of 57B16 mice were stable at various time points.
3. SD-OCT can see the existence of transplanted cells under the retina of transplanted mice, and can be confirmed by subsequent histological examination. Histological section can observe the survival of transplanted cells under the retina of rhodopsin - / mice, but hardly observe the migration and integration of cells into the retina of recipient mice. There was no significant difference in retinal functional examination (ERG) between mice (subretinal injection of PBS).
Two, research conclusion
1. Hypoxic culture conditions are conducive to the expansion of human retinal progenitor cells in vitro, and can maintain the ability of cell differentiation.
2. Data from SD-OCT measurements confirmed that rhodopsin-/mouse outer nuclear layer thickness gradually thinned after birth. The results of OCT were confirmed by both histological and quantitative detection of ERG function. SD-OCT can be used as a noninvasive, effective and reliable research tool for dynamic observation of retinal degeneration. The changing course of disease in animal models of sexual diseases.
3. Immunosuppression of rhodopsin-/mouse by cyclosporine can improve the survival of transplanted cells, but the transplanted cells did not migrate and integrate to the recipient retina during the observation period. There was no improvement in retinal function after transplantation.
【學(xué)位授予單位】：華中科技大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2012
【分類號】：R774.1

【共引文獻(xiàn)】

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