發(fā)布時間：2018-04-28 02:03

  本文選題：腦中風(fēng) + 小膠質(zhì)細(xì)胞增生��； 參考：《蘭州大學(xué)》2013年博士論文

【摘要】：小膠質(zhì)細(xì)胞是中樞神經(jīng)系統(tǒng)(Central nervous system, CNS)重要的免疫效應(yīng)細(xì)胞,它們通過監(jiān)測微環(huán)境的變化,參與維持中樞神經(jīng)系統(tǒng)的穩(wěn)態(tài)平衡。缺血性腦中風(fēng)能引起小膠質(zhì)細(xì)胞的迅速激活,活化小膠質(zhì)細(xì)胞在形態(tài)、抗原表達(dá)、功能行為等方面發(fā)生改變,尤其是他們在損傷區(qū)發(fā)生細(xì)胞增殖和聚集現(xiàn)象,小膠質(zhì)細(xì)胞的這些反應(yīng)被稱為“小膠質(zhì)細(xì)胞增生”。目前對這些增殖的小膠質(zhì)細(xì)胞的來源仍有爭議,有研究者認(rèn)為小膠質(zhì)細(xì)胞增生主要是通過小膠質(zhì)細(xì)胞的自我更新得以維持。而另外一些報道稱骨髓來源的一些祖細(xì)胞參與了小膠質(zhì)細(xì)胞增生的過程,但這些研究都是基于輻射骨髓移植動物模型,而輻射和骨髓移植可能會帶來血腦屏障的破壞等人為的影響,因此這些現(xiàn)象在生理?xiàng)l件下能否發(fā)生仍不清楚。 本論文利用中風(fēng)這一通常病理?xiàng)l件下既有血腦屏障破壞的的疾病模型,研究了小膠質(zhì)細(xì)胞在缺血后增生的主要來源。為了避免輻射等人為因素對動物正常生理活動的影響,本實(shí)驗(yàn)建立了兩種血液嵌合模型,并利用雙光子成像技術(shù)研究了缺血性腦中風(fēng)后亞急性期內(nèi)增殖小膠質(zhì)細(xì)胞的起源和動態(tài)變化,以及誘導(dǎo)其激活和增殖的影響因素。本論文的研究結(jié)果表明,正常健康動物體內(nèi)血液細(xì)胞無法通過完整的血腦屏障。然而腦中風(fēng)血腦屏障受損后,少量血液來源的Cx3crlGFP/+細(xì)胞能遷移進(jìn)入大腦實(shí)質(zhì)。雖然這些遷入的細(xì)胞與腦實(shí)質(zhì)內(nèi)小膠質(zhì)細(xì)胞一樣有熒光標(biāo)記,但是它們表現(xiàn)出與本地小膠質(zhì)細(xì)胞不同的表型特征和動力學(xué)反應(yīng)。缺血損傷后進(jìn)入腦實(shí)質(zhì)的血源細(xì)胞數(shù)量很少,前5天發(fā)生遷移的細(xì)胞數(shù)量增加,隨后逐漸減少。由于這些遷移細(xì)胞無法進(jìn)行自我增殖,并且隨著損傷時間的推移逐漸發(fā)生凋亡,因此血源遷移細(xì)胞無法長期存活。與此相反,免疫組織化學(xué)染色和雙光子活體成像結(jié)果顯示,缺血激活的本地小膠質(zhì)細(xì)胞持續(xù)向損傷區(qū)聚集并能進(jìn)行分裂增殖,而且這些細(xì)胞在損傷后一周內(nèi)保持持續(xù)增加的趨勢。因此,本地小膠質(zhì)細(xì)胞的自我增殖是小膠質(zhì)細(xì)胞增生的主要來源。另外,研究還發(fā)現(xiàn)血源Cx3erlGFP/+細(xì)胞的遷移和本地小膠質(zhì)細(xì)胞的激活和增殖與損傷區(qū)血腦屏障的開放范圍有關(guān)。本論文的研究結(jié)果揭示了血源Cx3erlGFP/+遷移細(xì)胞和本地小膠質(zhì)細(xì)胞代表著兩類不同的細(xì)胞種群,這兩類細(xì)胞可能具有不同的功能和治療潛力。
[Abstract]:Microglia are important immune effector cells in central nervous system (CNS). They play an important role in maintaining the homeostasis of CNS by monitoring the changes of microenvironment. Ischemic stroke can cause the rapid activation of microglia, the activation of microglia in morphology, antigen expression, functional behavior and other changes, especially in the injured areas of cell proliferation and aggregation. These reactions in microglia are called microglial proliferation. At present, the origin of these proliferating microglia is still controversial. Some researchers believe that microglial proliferation is mainly maintained through the self-renewal of microglia. Other reports suggest that some progenitor cells from bone marrow are involved in the process of microglia proliferation, but these studies are based on radiation bone marrow transplantation animal models. Radiation and bone marrow transplantation may result in the damage of blood-brain barrier and so on, so it is not clear whether these phenomena can occur under physiological conditions. In this study, the main sources of microglia proliferation after ischemia were studied by using the model of stroke, which is a common pathological disease with the destruction of the blood-brain barrier. In order to avoid the effects of human factors such as radiation on the normal physiological activities of animals, two blood chimeric models were established. The origin and dynamic changes of proliferative microglia during the subacute phase after ischemic stroke and the factors influencing their activation and proliferation were studied by using two-photon imaging technique. The results of this study suggest that blood cells in healthy animals cannot pass through the complete blood-brain barrier. However, after stroke the blood-brain barrier is damaged, a small number of blood-derived Cx3crlGFP/ cells can migrate into the brain's parenchyma. Although these migrating cells have the same fluorescence labeling as microglia in brain parenchyma, they exhibit different phenotypic characteristics and dynamic responses than native microglia. The number of hematopoietic cells entering the cerebral parenchyma was very small after ischemia injury, and the number of cells migrating increased in the first 5 days, then decreased gradually. These migration cells could not survive for a long time because they could not self-proliferate and apoptosis gradually occurred with the damage time. In contrast, immunohistochemical staining and two-photon imaging showed that ischemic activated native microglia continued to accumulate into the damaged area and to divide and proliferate. And these cells continued to increase for a week after injury. Therefore, the self-proliferation of native microglia is the main source of microglial proliferation. In addition, we also found that the migration of blood-derived Cx3erlGFP/ cells and the activation and proliferation of native microglia were related to the opening of blood-brain barrier. The results of this study reveal that Cx3erlGFP/ migration cells and native microglia represent two different cell populations, and these two types of cells may have different functions and therapeutic potential.
【學(xué)位授予單位】：蘭州大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2013
【分類號】：R743.3

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本文編號：1813298