本文選題：缺血性卒中 + 神經(jīng)干細(xì)胞��； 參考：《第二軍醫(yī)大學(xué)》2017年博士論文

【摘要】：腦卒中主要發(fā)生在老年人群中,是老年人群致殘的重要原因之一,以腦梗死為主。隨著我國人口進(jìn)入老齡化時代,腦梗死患病率逐年升高,嚴(yán)重降低了患者的生存質(zhì)量和平均壽命,嚴(yán)重危害老年人的身體健康,給國民經(jīng)濟(jì)帶來沉重的負(fù)擔(dān)。目前臨床上傳統(tǒng)抗凝、溶栓、神經(jīng)保護(hù)以及后期的康復(fù)等治療效果有限,大部分腦卒中患者后期仍留下各種偏癱、失語等不同程度的經(jīng)功能障礙后遺癥。因此,尋找新的治療方法促進(jìn)缺血性腦血管病患者神經(jīng)功能的恢復(fù)已成為當(dāng)今研究的重點[1],在過去的四十年里,腦卒中發(fā)病率在發(fā)達(dá)國家降低了43%,而在發(fā)展中國家卻增長了100%,發(fā)生于這些國家的腦卒中死亡數(shù)約占腦卒中死亡總數(shù)的87%[2]。若沒有有效干預(yù)措施,至2030年全球腦卒中死亡人數(shù)將增加至780萬[3]。腦卒中患者中87%是缺血性腦梗死[4]。多種疾病均可能導(dǎo)致缺血性卒中,而其最重要的病因包括大動脈粥樣硬化(血管),心源性腦栓塞,腦小血管病(微血管病變)。不太常見的病因是頸部動脈夾層動脈瘤、腦血管炎、凝血功能障礙性疾病、血液病等。即使在完成相關(guān)診斷檢查仍有部分缺血性腦卒中患者無法明確病因。對于急性缺血性腦梗死,FDA只認(rèn)證了早期溶栓作為治療手段。但由于時間窗的限制,95%以上的患者無法得到溶栓治療[5]。因此,探索新的、能讓更多患者受益的缺血性卒中治療策略具有極其重要的現(xiàn)實意義。近年來,神經(jīng)干細(xì)胞(Neural stem cells,NSCs)在腦梗死治療中的應(yīng)用研究,為解決這一難題提供了新的思路和方法。國內(nèi)外已有相關(guān)研究證實了NSCSs具有顯著的神經(jīng)保護(hù)作用[6,7]。1.在急性腦梗死的研究中,NSCs對于血管內(nèi)皮細(xì)胞的保護(hù)作用尚不明確。腦微血管內(nèi)皮細(xì)胞(BMECs)不僅僅是血管腔的內(nèi)襯,還能分泌活性物質(zhì)影響神經(jīng)元的生存。我們針對NSCs能否有效修復(fù)缺血損傷的BMECs開展了進(jìn)一步研究。2.我們發(fā)現(xiàn)NSCs可以通過直接或間接接觸的方式保護(hù)缺血損傷的內(nèi)皮細(xì)胞:在前期實驗中,我們成功分離和培養(yǎng)了NSCs和BMECs;為了進(jìn)一步模擬缺血損傷中內(nèi)皮細(xì)胞所處的病理生理條件,我們對BMEC實施了缺糖缺氧/復(fù)糖復(fù)氧(oxygen-glucose deprivation,OGD)的類缺血再灌注損傷處理,并建立了這兩種細(xì)胞的共培養(yǎng)模型;證實了NSCs能有效保護(hù)和修復(fù)OGD-BMECs。那么,NSCs是通過什么機制來發(fā)揮這種保護(hù)作用的呢?早期的研究認(rèn)為干細(xì)胞分化和細(xì)胞融合是修復(fù)的可能機制,但是當(dāng)前更多的研究對以上兩種觀點提出了置疑。研究發(fā)現(xiàn),用NSCs處理中動脈栓塞(middle cerebral artery occlusion,MCAO)鼠模型,其功能評分得到很大改善,但GFP標(biāo)記顯示能夠真正到達(dá)病灶分化成神經(jīng)元的NSCs數(shù)量非常有限[8]。這些外源性NSCSs來源的神經(jīng)元細(xì)胞無法解釋小鼠功能評分的顯著改善。因此,促使人們探尋NSCSs的其它可能保護(hù)機制。3.PI3K/Akt/GSK-3b/m TOR信號通路參與了代謝調(diào)節(jié)、細(xì)胞生長和存活等多種重要功能。PI3K活性形式為一種原癌基因,多種腫瘤疾病發(fā)現(xiàn)有PI3K的異常擴(kuò)增和突變。在哺乳動物細(xì)胞中,基于結(jié)構(gòu)、分布及活化機制的不同,PI3K可被分為三類,I類PI3Ks分為Ia和Ib兩類[9]。IA類PI3K可被受體酪氨酸激酶激活,而Ib類PI3K則被G蛋白偶聯(lián)受體激活。這些PI3K均是由調(diào)節(jié)亞基(如p85)和催化亞基(如P110)組成的異源二聚體。PI3K參與控制細(xì)胞的遷移和血管生成。PI3K產(chǎn)生的磷脂第二信使參與細(xì)胞內(nèi)信號轉(zhuǎn)導(dǎo)過程中的多個步驟。PI3K可磷酸化和激活A(yù)kt,將其定位在質(zhì)膜上[10]。Akt是PI3K調(diào)節(jié)細(xì)胞生長和細(xì)胞遷移的主要下游靶因子。在人體內(nèi)有三種亞型:Akt1、Akt2和Akt3。PI3K產(chǎn)生的PIP3結(jié)合Akt并導(dǎo)致Akt的膜聚集,并通過其PH結(jié)構(gòu)域結(jié)合磷酸肌醇依賴性蛋白激酶1(PDK1),然后PDK1磷酸化Akt激酶結(jié)構(gòu)域[11]。為充分激活A(yù)kt,也需PDK2磷酸化AKT羧基端調(diào)節(jié)區(qū)域(AKT1在絲氨酸473位)。一旦激活,AKT就進(jìn)入細(xì)胞質(zhì)和細(xì)胞核,產(chǎn)生一系列下游影響,如激活CREB,抑制p27,將FOXO定位于細(xì)胞質(zhì)中,激活ptdins-3ps,影響P70和4EBP1的轉(zhuǎn)錄導(dǎo)致m TOR復(fù)合物的聚集和激活。m TOR調(diào)節(jié)核糖體蛋白S6激酶和真核翻譯起始因子4E結(jié)合蛋白1進(jìn)而引起翻譯起始因子e IF4E的釋放。糖原合成酶激酶-3β(GSK-3β)是一種絲氨酸/蘇氨酸激酶,已有研究證明該激酶參與細(xì)胞增殖、細(xì)胞程序性死亡,胚胎發(fā)生,調(diào)節(jié)晝夜節(jié)律。GSK-3β屬于保守絲氨酸/蘇氨酸激酶家族,它的活性可以在Tyr殘基被磷酸化后激活,而其活性會在Ser9殘基部位被磷酸化后抑制,多種細(xì)胞功能的調(diào)節(jié)均有GSK-3β的參與,包括基因表達(dá)、代謝、和維持細(xì)胞骨架的完整性,GSK-3β是一種細(xì)胞生長、增殖的負(fù)性調(diào)控因子[12]。許多已知因素包括EGF,shh,IGF-1、胰島素和Cam等均可激活PI3K/Akt通路,而PTEN,HB9等可拮抗該通路表達(dá)[7,11,13-16]。越來越多的證據(jù)顯示,NSCSs與BMEC直接接觸共培養(yǎng)對PI3K/Akt/GSK-3β/m TOR信號通路的影響可能增加了NSCs對內(nèi)皮細(xì)胞功能的調(diào)節(jié)作用[9]。研究該通路在此過程中作用機制,可望為腦卒中的合理預(yù)防、逆轉(zhuǎn)提供重要依據(jù)。本課題擬通過體內(nèi)外的缺血缺氧模型探討神經(jīng)干細(xì)胞在卒中病變中的神經(jīng)保護(hù)機制及PI3K/Akt/GSK-3β/m TOR信號通路的影響。實驗方法1.原代培養(yǎng)神經(jīng)元2.不同濃度GSK-3β抑制劑TWS119不同濃度處理細(xì)胞,MTT法檢測神經(jīng)元活性變化3.MAP-2熒光染色后使用Image-J軟件計數(shù)神經(jīng)元突觸總長度變化4.Western Blot檢測Mcl-1、Bcl-2、Bax凋亡通路相關(guān)蛋白表達(dá)變化5.原代培養(yǎng)腦微血管內(nèi)皮細(xì)胞及胎鼠培養(yǎng)神經(jīng)干細(xì)胞,將BMECs置于氧糖剝奪環(huán)境中,兩種細(xì)胞使用Transwell小室進(jìn)行間接共培養(yǎng)6.Casepase-3凋亡相關(guān)酶活性及LDH酶活性檢測細(xì)胞損傷7.Western Blot及q-rt PCR檢測PI3K/AKT/GSK-3信號通路表達(dá)變化8.制作大腦中動脈栓塞模型在SD大鼠中模擬缺血性腦梗,設(shè)置假手術(shù)組,NSCs治療組,動物疾病模型組、PI3k抑制劑組進(jìn)行免疫組化染色等體內(nèi)實驗9.行為學(xué)及TTC染色明確腦梗模型建立10.HE染色、尼氏染色觀察神經(jīng)干細(xì)胞移植后腦組織形態(tài)學(xué)改變11.MAP-2、GAP-43、Sinapsin-1染色觀察神經(jīng)元、突觸重塑情況12.IBA-1、GFAP免疫組化觀察小膠質(zhì)細(xì)胞、星形膠質(zhì)細(xì)胞激活情況反映免疫激活狀態(tài)13.Beclin-1、LC-3免疫組化檢測自噬活性14.檢測細(xì)胞、動物模型中炎癥因子表達(dá)變化15.錯步實驗及黏膠移除實驗進(jìn)行腦梗后行為學(xué)觀察。結(jié)果1.MTT染色顯示細(xì)胞活性在氧糖剝奪環(huán)境中顯著降低,但GSK-3β抑制劑TWS119處理后神經(jīng)元活性提高2.GSK-3β抑制劑TWS119增加神經(jīng)元突觸總長度3.GSK-3β抑制劑TWS119能增加抗凋亡蛋白Mcl-1、Bcl-2的表達(dá),而下調(diào)促凋亡蛋白Bax4.GSK-3β抑制劑TWS119可使抗炎因子IL-10表達(dá)增加,而促炎因子IL-1β,IL-6及ICAM-1下降,炎癥因子IFN-γ表達(dá)未見明顯變化5.原代培養(yǎng)腦微血管內(nèi)皮細(xì)胞及胎鼠神經(jīng)干細(xì)胞使用Transwell小室進(jìn)行間接共培養(yǎng),其PI3K/AKT/GSK-3信號通路磷酸化水平增高,Casepase-3凋亡相關(guān)酶活性及LDH酶活性檢測提示細(xì)胞損傷較單純?nèi)毖Ｐ图?xì)胞組減輕6.制作大腦中動脈栓塞模型在SD大鼠中模擬缺血性腦梗,設(shè)置假手術(shù)組,NSCs治療組,動物疾病模型組進(jìn)行免疫組化染色等體內(nèi)實驗7.大鼠行為學(xué)、TTC染色明確腦梗模型建立8.HE染色、尼氏染色觀察神經(jīng)干細(xì)胞注射后腦組織核固縮、核碎裂及尼氏染色缺失等病理改變有所減輕9.MAP-2、GAP-43、Sinapsin-1染色觀察顯示細(xì)胞存活量在NSCs治療后明顯提高10.IBA-1、GFAP免疫組化觀察NSCs能降低缺血損傷引起的炎癥反應(yīng)細(xì)胞激活,自噬活性也降低11.NSCs治療后,動物模型中炎癥因子L-Selectin,leptin,MCP-1及TNFα表達(dá)降低,抗炎因子TIMP-1表達(dá)升高12.NSCs治療組大鼠行為學(xué)實驗中錯步數(shù)及黏膠移除所需時間均有所減少13.以上變化可被PI3k抑制劑LY294002部分逆轉(zhuǎn)結(jié)論抑制神經(jīng)元GSK-3β對氧糖剝奪環(huán)境下的神經(jīng)元產(chǎn)生保護(hù)作用,提高神經(jīng)元活性,使神經(jīng)元突觸長度變長,抑制凋亡活性。機體內(nèi)產(chǎn)生GSK-3β抑制作用的主要上游信號通路由PI3K/AKT介導(dǎo),神經(jīng)干細(xì)胞能激活氧糖剝奪環(huán)境下BMECs中該通路,同時通過抗凋亡、抗炎、抑制自噬等作用促進(jìn)MCAO模型鼠神經(jīng)功能恢復(fù)。這些作用部分被PI3K抑制劑LY294002所抵消,說明神經(jīng)干細(xì)胞通過PI3K/AKT/GSK-3β信號通路參與卒中損傷的神經(jīng)保護(hù)作用。
[Abstract]:Cerebral apoplexy is one of the main causes of the elderly population. It is one of the most important reasons for the disabled in the elderly. With the age of aging in China, the incidence of cerebral infarction is increasing year by year, which seriously reduces the life quality and average life span of the patients, seriously endangers the health of the elderly and brings heavy burden to the national economy. The therapeutic effect of traditional anticoagulant, thrombolytic, neuroprotective and later rehabilitation is limited, and most of the stroke patients still leave a variety of hemiplegia, aphasia and other dysfunctional sequelae. Therefore, looking for a new treatment method to promote the recovery of neural function of patients with ischemic cerebral blood tube disease has become the present research. In the past forty years, the incidence of stroke has decreased by 43% in developed countries, while in developing countries, the incidence of stroke has increased by 100% in the developing countries. The number of stroke deaths in these countries accounts for about 87%[2]. of the total number of stroke deaths in these countries without effective intervention, and the number of global stroke deaths will increase to 7 million 800 thousand [3]. stroke by 2030. 87% of the patients with ischemic cerebral infarction may cause ischemic stroke in many [4]. diseases. The most important causes include large atherosclerosis (vascular), cardiogenic cerebral embolism, and small vascular disease (microvascular disease). The most common causes are carotid artery dissecting aneurysm, cerebral vasculitis, coagulation dysfunction disease, and hematological diseases. Even in the completion of the related diagnosis, some patients with ischemic stroke are still unable to identify the cause. For acute ischemic cerebral infarction, FDA only certified early thrombolytic therapy. But because of the time window, more than 95% of the patients are unable to get thrombolytic therapy for [5].. In recent years, the application of Neural stem cells (NSCs) in the treatment of cerebral infarction has provided a new way of thinking and method to solve this problem. The relevant research at home and abroad has confirmed that NSCSs has a significant neuroprotective effect of [6,7].1. in the study of acute cerebral infarction. The protective effect of NSCs on vascular endothelial cells is not clear. Cerebral microvascular endothelial cells (BMECs) are not only the inner lining of the vascular cavity, but also secrete active substances to affect the survival of neurons. We have further studied whether NSCs can effectively repair the BMECs of ischemic damage. We found that NSCs can be directly or indirectly exposed. We successfully isolated and cultured NSCs and BMECs in the early experiments. In order to further simulate the pathophysiological conditions of endothelial cells in ischemic injury, we carried out ischemic reperfusion injury treatment for BMEC deficiency / hypoxia / reoxygenation (oxygen-glucose deprivation, OGD). A co culture model of these two cells has been established, and it has been confirmed that NSCs can effectively protect and repair OGD-BMECs.. What mechanism does NSCs use to play this protective effect? Early studies suggest that stem cell differentiation and cell fusion are possible mechanisms for repair, but more studies have questioned the above two views. It was found that the function score of the middle cerebral artery occlusion (MCAO) rat model was greatly improved with NSCs, but the GFP markers showed that the number of NSCs that could really reach the lesion differentiation into neurons was very limited and the number of the xenobiotic cells derived from exogenous NSCSs could not explain the significant improvement of the function score of the mice. Therefore, the other possible protective mechanism of NSCSs,.3.PI3K/Akt/GSK-3b/m TOR signaling pathway, is involved in metabolic regulation, cell growth and survival, such as cell growth and survival, as a proto oncogene, and a variety of tumor diseases are found to have abnormal amplification and mutation of PI3K. In mammalian cells, structure based, distribution Different from the activation mechanism, PI3K can be divided into three classes. Class I PI3Ks is divided into Ia and Ib two classes [9].IA PI3K can be activated by receptor tyrosine kinase, and Ib class PI3K is activated by G protein coupled receptors. These PI3K are heterogenous two polymers composed of regulatory subunits (such as p85) and catalytic subunits, which participate in the control of cell migration and angiogenesis. The phosphatidylcholine second messenger produced by.PI3K is involved in multiple steps in the intracellular signal transduction process.PI3K can phosphorylation and activation of Akt, which is located on the plasma membrane and [10].Akt is the main downstream target factor for PI3K regulating cell growth and cell migration. There are three subtypes in the human body: PIP3 binding Akt produced by Akt1, Akt2 and Akt3.PI3K and leading to Akt The membrane aggregates, and through its PH domain, binding the inositol phosphoric acid dependent protein kinase 1 (PDK1), and then PDK1 phosphorylated Akt kinase domain [11]. to fully activate Akt, and also the PDK2 phosphorylation of the AKT carboxyl terminal regulating region (AKT1 at the serine 473). Once activated, AKT enters the cell and nucleus, producing a series of downstream effects, such as activating CREB, Inhibition of p27, FOXO is located in the cytoplasm, activates ptdins-3ps, affects the transcription of P70 and 4EBP1, causes the aggregation of M TOR complexes and activates the.M TOR regulated ribosome S6 kinase and the eukaryotic translation initiation factor 4E binding protein 1, thus causing the release of the translation initiation factor E. The kinase, which has been proved to be involved in cell proliferation, programmed cell death, embryogenesis, and regulating the circadian rhythm of.GSK-3 beta, is a conservative serine / threonine kinase family, its activity can be activated after the phosphorylation of the Tyr residue, and its activity will be inhibited after the phosphorylation of the Ser9 residues and the regulation of a variety of cell functions. The participation of GSK-3 beta, including gene expression, metabolism, and maintenance of the integrity of cytoskeleton, GSK-3 beta is a cell growth, a negative regulator of proliferation, [12]., many known factors including EGF, Shh, IGF-1, insulin and Cam can activate PI3K/Akt pathway, and PTEN, HB9, etc. can antagonize the increasing evidence of this pathway to express [7,11,13-16].. The effect of direct contact between NSCSs and BMEC on PI3K/Akt/GSK-3 beta /m TOR signaling pathway may increase the regulatory role of NSCs on endothelial cell function and [9]. study the mechanism of this pathway in this pathway, which is expected to provide an important basis for the rational prevention and reversal of stroke. The neuroprotective mechanism of neural stem cells and the effect of PI3K/Akt/GSK-3 beta /m TOR signaling pathway in stroke disease. Experimental methods 1. primary cultured neurons 2. different concentrations of GSK-3 beta inhibitor TWS119 were treated with different concentrations of TWS119 cells, MTT assay was used to detect neuronal activity and 3.MAP-2 fluorescence staining was used to count the synapse total of neurons by Image-J software Length variation 4.Western Blot detection of Mcl-1, Bcl-2, Bax apoptosis pathway related protein expression changes 5. primary culture of brain microvascular endothelial cells and fetal rat culture neural stem cells, BMECs in oxygen deprivation environment, two cells using Transwell chamber for indirect co culture 6.Casepase-3 apoptosis related enzyme activity and LDH enzyme activity detection Cell injury 7.Western Blot and q-rt PCR detection of PI3K/AKT/GSK-3 signaling pathway expression change 8. to make cerebral artery embolism model in SD rats to simulate ischemic infarction in SD rats, set up sham operation group, NSCs treatment group, animal disease model group, PI3k inhibitor group with immunohistochemical staining in vivo and TTC staining to clear brain infarction model 10.HE staining was established. Nissl staining was used to observe the morphological changes of brain tissue after neural stem cell transplantation. 11.MAP-2, GAP-43, Sinapsin-1 staining was used to observe neurons, synaptic remodeling was observed in 12.IBA-1, GFAP immunohistochemistry was used to observe the microglia, the activation of astrocytes reflected the immune activation state 13.Beclin-1, and LC-3 immunochemistry was used to detect autophagy. Sex 14. detected cells, the expression of inflammatory factors in the animal model, the 15. error step experiment and the adhesive removal experiment to observe the post infarction behavior. Results 1.MTT staining showed that the cell activity was significantly reduced in the oxygen deprivation environment, but the activity of GSK-3 beta inhibitor TWS119 was higher than that of 2.GSK-3 beta inhibitor TWS119 to increase the neuron synapse. The total length of 3.GSK-3 beta inhibitor TWS119 could increase the expression of anti apoptotic protein Mcl-1 and Bcl-2, while the down-regulation of Bax4.GSK-3 beta inhibitor TWS119 could increase the expression of anti inflammatory factor IL-10, while the proinflammatory factor IL-1 beta, IL-6 and ICAM-1 decreased, and the expression of inflammatory factor IFN- gamma did not significantly change 5. primary cultured cerebral microvascular endothelial cells and fetal rat God. Through indirect co culture of Transwell cells through the use of stem cells, the level of phosphorylation of the PI3K/AKT/GSK-3 signaling pathway increased, the activity of Casepase-3 apoptosis related enzymes and the activity of LDH enzyme suggested that the cell damage was reduced by 6. to make the middle cerebral artery embolism model in the SD rats to simulate the ischemic cerebral infarction in the SD rats and set up the sham operation. Group, NSCs treatment group, animal disease model group with immunohistochemical staining and other in vivo experiments of 7. rats, TTC staining clear brain infarction model established 8.HE staining, Nissl staining observation of neural stem cells after injection of brain tissue nuclear pyknosis, nuclear fragmentation and Nissl staining loss and other pathological changes to reduce 9.MAP-2, GAP-43, Sinapsin-1 staining observed obvious The survival of the cells was significantly increased by 10.IBA-1 after NSCs treatment. NSCs could reduce the activation of inflammatory cells induced by ischemic injury, and the autophagy activity also reduced 11.NSCs treatment. The expression of inflammatory factors L-Selectin, leptin, MCP-1 and TNF alpha in the animal model decreased, and the expression of anti inflammatory factor TIMP-1 increased in the 12.NSCs treatment group. The time required for the number of wrong steps and the removal of sticky glue in the behavioral experiment can be reduced by more than 13., which can be reversed by the partial reversal of the PI3k inhibitor LY294002, which inhibits the protective effect of GSK-3 beta on neurons in the oxygen deprivation environment, improves the activity of neurons, increases the length of the synapse and inhibits the apoptosis activity, and produces GSK-3 in the body. The main upstream signal of beta inhibition is mediated by route PI3K/AKT. Neural stem cells can activate the pathway of BMECs in the oxygen deprivation environment, and promote the recovery of neural function in MCAO model rats by anti apoptosis, anti-inflammatory and autophagy. These effects are partly offset by PI3K inhibitor LY294002, indicating that neural stem cells pass through PI3K/AKT/G. SK-3 beta signaling pathway is involved in the neuroprotective effect of stroke injury.
【學(xué)位授予單位】：第二軍醫(yī)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2017
【分類號】：R743.3

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