【摘要】：由于成體大腦自我修復(fù)能力有限,在經(jīng)歷創(chuàng)傷或者疾病之后無法通過自身來彌補(bǔ)損傷神經(jīng)元的丟失,因此大量的研究試圖通過移植外源的胚胎腦組織塊來替代損傷的腦區(qū),進(jìn)而促進(jìn)相應(yīng)的大腦損傷功能的恢復(fù)。這些研究結(jié)果表明移植的神經(jīng)元不僅能夠重建受體大腦受損的神經(jīng)環(huán)路并且能促進(jìn)皮層功能的恢復(fù)。一個(gè)成功的移植不只要重建受損的神經(jīng)元,還要重建其他的例如膠質(zhì)細(xì)胞等細(xì)胞群體。這其中就包括影響移植物存活和突觸連接、重塑的關(guān)鍵細(xì)胞:小膠質(zhì)細(xì)胞。作為中樞神經(jīng)系統(tǒng)內(nèi)具有免疫活性的一類細(xì)胞,小膠質(zhì)細(xì)胞在不同生理病理?xiàng)l件下的大腦中具有多種多樣的功能。此外在不同的病理?xiàng)l件下的成體大腦內(nèi),激活態(tài)的小膠質(zhì)細(xì)胞可以有不同的來源。雖然在正常和病理?xiàng)l件下的大腦中,小膠質(zhì)細(xì)胞的動(dòng)態(tài)變化和來源情況已經(jīng)被描述的很清楚,但是在移植的胚胎腦組織塊中其形態(tài)和數(shù)量變化的情況還不是很清楚。本論文利用小膠質(zhì)細(xì)胞特異性表達(dá)綠色熒光蛋白的轉(zhuǎn)基因小鼠和雙光子活體成像技術(shù)來研究胚胎腦組織塊移植模型中移植小膠質(zhì)細(xì)胞的存活情況和受體來源的小膠質(zhì)細(xì)胞的侵入、增殖和分化的過程。同時(shí),結(jié)合異種共生血液嵌合模型研究移植塊內(nèi)受體小膠質(zhì)細(xì)胞的來源和命運(yùn)。我們的結(jié)果表明移植的神經(jīng)元能夠成功在受體大腦內(nèi)存活和分化。和移植的神經(jīng)元的命運(yùn)不同,胚胎腦組織移植塊內(nèi)的小膠質(zhì)細(xì)胞卻在移植到受體大腦內(nèi)后迅速的消失。相反,移植區(qū)域里分布的小膠質(zhì)細(xì)胞被證實(shí)是來源于侵入的受體細(xì)胞。同時(shí),侵入的小膠質(zhì)細(xì)胞在經(jīng)歷增殖和劇烈的形態(tài)學(xué)變化后,最終慢慢的分化成為靜息態(tài)的狀態(tài)。血液嵌合模型則表明這些侵入的受體來源的小膠質(zhì)細(xì)胞主要來源于大腦實(shí)質(zhì)。綜上,我們的結(jié)果揭示了受體大腦實(shí)質(zhì)來源的小膠質(zhì)細(xì)胞侵入到移植區(qū)域后恢復(fù)該區(qū)域的小膠質(zhì)細(xì)胞群落的過程,該結(jié)果揭示了胚胎移植塊內(nèi)的小膠質(zhì)細(xì)胞的來源和分化的問題,為該移植方法在臨床上的應(yīng)用提供了一定的理論支持。
[Abstract]:Due to the limited ability of the adult brain to repair itself, it is not possible to compensate for the loss of injured neurons by itself after experiencing trauma or disease. Therefore, a large number of studies have attempted to replace the damaged brain regions by transplanting exogenous embryonic brain tissue blocks. And then promote the recovery of brain injury function. These results suggest that the transplanted neurons can not only reconstruct the injured neural loop of the receptor brain, but also promote the recovery of cortical function. A successful transplant involves not only rebuilding damaged neurons, but also other cell groups, such as glial cells. These include key cells that affect graft survival and synaptic connections, remodeling: microglia. As a class of immune cells in the central nervous system, microglia have a variety of functions in the brain under different physiological and pathological conditions. In addition, activated microglia may come from different sources in the adult brain under different pathological conditions. Although the dynamic changes and origin of microglia in the normal and pathological brain have been described clearly, the morphological and quantitative changes of microglia in the transplanted embryonic brain mass are not very clear. In this paper, the microglia specific expression of green fluorescent protein in transgenic mice and two-photon imaging were used to study the survival of transplanted microglia and the small recipient source in the model of embryonic brain tissue transplantation. The invasion of glial cells, The process of proliferation and differentiation. At the same time, the origin and fate of the receptor microglia in the graft block were studied by using the blood chimerism model of xenosymbiosis. Our results suggest that the transplanted neurons can successfully survive and differentiate in the receptor brain. Unlike the fate of the transplanted neurons, the microglia in the embryonic brain tissue graft rapidly disappeared after being transplanted into the recipient brain. Instead, microglia distributed in the transplant area were confirmed to be derived from invading receptor cells. At the same time, the invasive microglia gradually differentiated into a resting state after experiencing proliferation and severe morphological changes. The blood chimerism model showed that the microglia derived from these invading receptors were mainly derived from the brain parenchyma. In summary, our results reveal the process by which microglia from parenchymal sources of the receptor brain invade into the transplanted region and recover the microglia community in that region. The results reveal the origin and differentiation of microglia in embryo transfer and provide some theoretical support for the clinical application of this method.
【學(xué)位授予單位】：蘭州大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R741

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