胚胎脑组织移植块中小胶质细胞的来源与分化

发布时间：2018-08-16 11:27

【摘要】：由于成体大脑自我修复能力有限,在经历创伤或者疾病之后无法通过自身来弥补损伤神经元的丢失,因此大量的研究试图通过移植外源的胚胎脑组织块来替代损伤的脑区,进而促进相应的大脑损伤功能的恢复。这些研究结果表明移植的神经元不仅能够重建受体大脑受损的神经环路并且能促进皮层功能的恢复。一个成功的移植不只要重建受损的神经元,还要重建其他的例如胶质细胞等细胞群体。这其中就包括影响移植物存活和突触连接、重塑的关键细胞:小胶质细胞。作为中枢神经系统内具有免疫活性的一类细胞,小胶质细胞在不同生理病理条件下的大脑中具有多种多样的功能。此外在不同的病理条件下的成体大脑内,激活态的小胶质细胞可以有不同的来源。虽然在正常和病理条件下的大脑中,小胶质细胞的动态变化和来源情况已经被描述的很清楚,但是在移植的胚胎脑组织块中其形态和数量变化的情况还不是很清楚。本论文利用小胶质细胞特异性表达绿色荧光蛋白的转基因小鼠和双光子活体成像技术来研究胚胎脑组织块移植模型中移植小胶质细胞的存活情况和受体来源的小胶质细胞的侵入、增殖和分化的过程。同时,结合异种共生血液嵌合模型研究移植块内受体小胶质细胞的来源和命运。我们的结果表明移植的神经元能够成功在受体大脑内存活和分化。和移植的神经元的命运不同,胚胎脑组织移植块内的小胶质细胞却在移植到受体大脑内后迅速的消失。相反,移植区域里分布的小胶质细胞被证实是来源于侵入的受体细胞。同时,侵入的小胶质细胞在经历增殖和剧烈的形态学变化后,最终慢慢的分化成为静息态的状态。血液嵌合模型则表明这些侵入的受体来源的小胶质细胞主要来源于大脑实质。综上,我们的结果揭示了受体大脑实质来源的小胶质细胞侵入到移植区域后恢复该区域的小胶质细胞群落的过程,该结果揭示了胚胎移植块内的小胶质细胞的来源和分化的问题,为该移植方法在临床上的应用提供了一定的理论支持。
[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.
【学位授予单位】：兰州大学
【学位级别】：博士
【学位授予年份】：2016
【分类号】：R741

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