本文選題：上皮組織 + 細(xì)胞模型�。� 參考：《上海交通大學(xué)》2015年博士論文

【摘要】：上皮組織是由緊密粘連的上皮細(xì)胞和極少量細(xì)胞間質(zhì)構(gòu)成的基本組織。它可以防止生物體受到外界環(huán)境中物理化學(xué)作用的侵害。上皮組織形態(tài)變化在胚胎形成、組織發(fā)育、疾病發(fā)生,尤其是癌癥的侵潤轉(zhuǎn)移中起重要作用。人類癌癥約有90%始于上皮組織的細(xì)胞變異。因此,對上皮組織的研究有利于幫助我們更加深入理解器官發(fā)育和腫瘤侵潤等重要生物學(xué)過程。本論文應(yīng)用梁杰教授實驗室開發(fā)的動態(tài)二維細(xì)胞模型,研究了不同系統(tǒng)中上皮組織形態(tài)發(fā)生發(fā)展的調(diào)節(jié)機制。其中包括增殖上皮組織的細(xì)胞拓?fù)浣Y(jié)構(gòu)調(diào)節(jié)機制,果蠅翅膀的形態(tài)延展機制,以及腫瘤侵潤的力學(xué)調(diào)控機制。研究上皮組織結(jié)構(gòu)和形態(tài)發(fā)生的二維細(xì)胞模型包含細(xì)胞的幾何特性和力學(xué)特性。此外,模型引入了單個細(xì)胞個體的性質(zhì)(如生長率、死亡率、分裂面、胞內(nèi)蛋白濃度等)以及多個細(xì)胞間的性質(zhì)(如細(xì)胞間力學(xué)作用,拓?fù)浞答佔饔玫?。此外,模型包含了組織動態(tài)生長過程中可能發(fā)生的拓?fù)浣Y(jié)構(gòu)變化。應(yīng)用細(xì)胞模型模擬增殖上皮組織生長分裂的結(jié)果顯示,細(xì)胞形態(tài)與實驗觀測吻合。細(xì)胞模型的建立為我們有效研究上皮組織結(jié)構(gòu)和形態(tài)的發(fā)生發(fā)展奠定了基礎(chǔ)。首先,本論文研究了增殖上皮組織細(xì)胞拓?fù)浣Y(jié)構(gòu)的調(diào)節(jié)機制。在正常增殖上皮組織中,細(xì)胞分裂和細(xì)胞重組可以調(diào)節(jié)生成自然界觀測到的具有一致守恒的細(xì)胞拓?fù)浣Y(jié)構(gòu)分布。選取不同的細(xì)胞分裂面(最大邊分裂和正交分裂),可以形成自然界觀測到的不同物種間細(xì)胞多邊形比率不同的特點。其中,最大邊分裂具有隨機性,正交分裂具有確定性。只有當(dāng)細(xì)胞具有“記憶”并持續(xù)進(jìn)行正交分裂時,正交分裂才可以顯著影響最終的細(xì)胞拓?fù)浣Y(jié)構(gòu)分布。在突變上皮組織中,研究結(jié)果表明,只有當(dāng)邊界細(xì)胞張力增大并結(jié)合不同的細(xì)胞增值速率時才可以重現(xiàn)實驗觀測的細(xì)胞拓?fù)浣Y(jié)構(gòu)分布偏移。其次,本論文研究了果蠅翅膀在發(fā)育過程中組織延展的調(diào)節(jié)機制。研究結(jié)果顯示,在果蠅發(fā)育至成蟲15-24小時期間,有向分裂、有向受力、和細(xì)胞體積減小共同調(diào)節(jié)組織延展,但它們作用不同。有向分裂和有向受力在組織延展過程中充當(dāng)有向信號,引導(dǎo)組織沿PD軸延展。此外,本研究首次發(fā)現(xiàn)增殖過程中細(xì)胞體積減小對組織延展的全新調(diào)控機制。細(xì)胞體積減小本身不能引導(dǎo)組織延展,因為它不具有任何方向信息。然而,當(dāng)與有向信號相結(jié)合(如細(xì)胞有向分裂和有向受力等),細(xì)胞體積減小可以顯著促進(jìn)組織延展的程度。最后,本論文研究了腫瘤侵潤的力學(xué)作用機制。研究結(jié)果顯示,當(dāng)癌細(xì)胞與胞外基質(zhì)的粘連力增強,并且與腫瘤細(xì)胞的粘連力降低時,腫瘤發(fā)生明顯的侵潤性行為。胞外基質(zhì)細(xì)胞剛度增加時,會促進(jìn)已發(fā)生侵潤的腫瘤細(xì)胞進(jìn)一步移動擴散。當(dāng)然,胞外基質(zhì)力學(xué)特性影響腫瘤侵潤組織形態(tài)的前提是腫瘤組織本身已具有侵潤能力。此外,胞外基質(zhì)細(xì)胞剛度的增加還可以影響侵潤性腫瘤細(xì)胞形狀,使得癌細(xì)胞伸長,具有更高的靈活性和遷移能力。綜上所述,本論文應(yīng)用二維細(xì)胞模型,研究了不同上皮系統(tǒng)中細(xì)胞和組織形態(tài)發(fā)生發(fā)展的調(diào)節(jié)機制。首先,在增殖上皮組織的細(xì)胞拓?fù)浣Y(jié)構(gòu)的調(diào)節(jié)機制研究中,本論文首次提出了細(xì)胞分裂面在形成正常增殖上皮組織中不同物種間細(xì)胞多邊形比率差異性的調(diào)控作用,首次提出并模擬驗證了邊界力學(xué)變化引起突變上皮組織中邊界增殖細(xì)胞拓?fù)浣Y(jié)構(gòu)分布發(fā)生偏移的假說。其次,在簡單上皮系統(tǒng)果蠅翅膀的形態(tài)延展機制研究中,本論文首次定量研究了有向分裂和有向受力作為有向信號引導(dǎo)果蠅翅膀延展的作用,并且首次發(fā)現(xiàn)細(xì)胞體積減小在果蠅翅膀形態(tài)延展中的關(guān)鍵調(diào)控作用。最后,在復(fù)雜上皮系統(tǒng)腫瘤侵潤的力學(xué)調(diào)控機制研究中,本論文首次發(fā)現(xiàn)了胞外基質(zhì)力學(xué)性能變化對腫瘤侵潤的調(diào)控作用,并發(fā)現(xiàn)胞外基質(zhì)力學(xué)性能改變可以反過來影響侵潤性腫瘤細(xì)胞的形狀。這些研究結(jié)果在臨床治療中具有重要指導(dǎo)意義。
[Abstract]:Epithelial tissue is a basic tissue composed of closely adherent epithelial cells and very small amounts of interstitial cells. It prevents the organism from being attacked by the physical and chemical effects of the external environment. The morphological changes of epithelial tissue play an important role in embryo formation, tissue development, disease, especially cancer invasion and metastasis. There are about 90 human cancers. The study of epithelial tissue will help us to understand the important biological processes such as organ development and tumor invasion. This paper uses the dynamic two-dimensional cell model developed by Professor Liang Jie's laboratory to study the regulation mechanism of epithelial tissue formation and development in different systems. It includes the regulatory mechanism of cell topological structure of proliferating epithelial tissue, the morphological extension mechanism of Drosophila wings, and the mechanical regulation mechanism of tumor invasion. The two-dimensional cell model of epithelial tissue structure and morphogenesis includes the geometric and mechanical properties of the cells. In addition, the model introduces the properties of individual cells (such as birth). Long rate, mortality, cleavage, intracellular protein concentration, as well as the properties of multiple cells (such as intercellular mechanics, topological feedback, etc.). Furthermore, the model contains the possible topological structure changes during the dynamic growth of tissue. The establishment of cell model lays a foundation for our effective study on the development of epithelial tissue structure and morphology. First, this paper studies the regulation mechanism of the topological structure of epithelial cells of proliferating epithelial tissue. In normal proliferating epithelial tissue, cell division and cell recombination can regulate the formation of natural observation in nature. The distribution of the topological structure of the conserved cells. The selection of different cell division surfaces (maximum edge division and Orthogonal Division) can form the characteristics of different species of cell polygons between different species observed in nature. The maximum edge division is random and the Orthogonal Division is definite. Only when the cell has "memory" and continues to carry on In the orthonormal division, the Orthogonal Division can significantly affect the final distribution of the cell topology. In the mutant epithelial tissue, the results show that the distribution of the topological structure of the cells can be reproduced only when the tension of the boundary cells is increased and the rate of cell increment is combined. Secondly, this paper studies the wings of Drosophila melanogaster. The regulatory mechanism of tissue extension during development. The results show that during the 15-24 hour period of fruit flies to adult, there is a directional division, a directed force, and a decrease in the volume of cells, but they act differently. The directed division and the directed force act as the directed signal during the tissue extension, and the guiding tissue extends along the PD axis. In addition, this study is the first to find a new regulatory mechanism for cell volume reduction and tissue extension during the proliferation process. The decrease of cell volume itself does not lead to tissue extension because it does not have any direction information. However, when combined with a directed signal (such as cell division and directed force, such as cells), the cell volume can be significantly promoted. In the end, the mechanical mechanism of tumor invasion was studied in this paper. The results showed that when the adhesion of the cancer cells and the extracellular matrix was enhanced and the adhesion of the tumor cells decreased, the tumor had obvious invasion behavior. When the extracellular matrix cell stiffness increased, the tumor cells that had been embellish were promoted into the tumor cells. In addition, the increase in the stiffness of extracellular matrix cells can also affect the shape of invasive tumor cells, which makes the cancer cells elongate and have higher flexibility and mobility. The regulation mechanism of cell and tissue morphogenesis in different epithelial systems was studied by using a two-dimensional cell model. First, in the study of the regulatory mechanism of the cell topology of proliferating epithelial tissue, the difference of cell polygon ratio between different species in the formation of normal proliferating epithelium was first proposed in this paper. For the first time, the hypothesis of the migration of the topological structure of the boundary proliferating cells in the mutant epithelial tissue caused by the change of boundary mechanics was first proposed and simulated. Secondly, in the study of the morphological extension mechanism of the wings of the simple epithelia, this paper first quantitatively studied the directed division and the directed force as the directed signal. The role of the Drosophila wings extension, and the first discovery of the key regulatory role of cell volume decrease in the morphological ductility of Drosophila wings. Finally, in the study of the mechanical regulation mechanism of the invasion of the complex epithelial tumor, this paper first discovered the regulation of the changes in the mechanical properties of the extracellular matrix on the tumor invasion and the discovery of the extracellular matrix force. Changes in performance can in turn affect the shape of invasive tumor cells. These findings have important guiding significance in clinical treatment.
【學(xué)位授予單位】：上海交通大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2015
【分類號】：R730.2

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