上皮组织形态变化建模及其在组织生长和肿瘤侵润中的应用

发布时间：2018-06-27 13:16

本文选题：上皮组织 + 细胞模型　；参考：《上海交通大学》2015年博士论文

【摘要】：上皮组织是由紧密粘连的上皮细胞和极少量细胞间质构成的基本组织。它可以防止生物体受到外界环境中物理化学作用的侵害。上皮组织形态变化在胚胎形成、组织发育、疾病发生,尤其是癌症的侵润转移中起重要作用。人类癌症约有90%始于上皮组织的细胞变异。因此,对上皮组织的研究有利于帮助我们更加深入理解器官发育和肿瘤侵润等重要生物学过程。本论文应用梁杰教授实验室开发的动态二维细胞模型,研究了不同系统中上皮组织形态发生发展的调节机制。其中包括增殖上皮组织的细胞拓扑结构调节机制,果蝇翅膀的形态延展机制,以及肿瘤侵润的力学调控机制。研究上皮组织结构和形态发生的二维细胞模型包含细胞的几何特性和力学特性。此外,模型引入了单个细胞个体的性质(如生长率、死亡率、分裂面、胞内蛋白浓度等)以及多个细胞间的性质(如细胞间力学作用,拓扑反馈作用等)。此外,模型包含了组织动态生长过程中可能发生的拓扑结构变化。应用细胞模型模拟增殖上皮组织生长分裂的结果显示,细胞形态与实验观测吻合。细胞模型的建立为我们有效研究上皮组织结构和形态的发生发展奠定了基础。首先,本论文研究了增殖上皮组织细胞拓扑结构的调节机制。在正常增殖上皮组织中,细胞分裂和细胞重组可以调节生成自然界观测到的具有一致守恒的细胞拓扑结构分布。选取不同的细胞分裂面(最大边分裂和正交分裂),可以形成自然界观测到的不同物种间细胞多边形比率不同的特点。其中,最大边分裂具有随机性,正交分裂具有确定性。只有当细胞具有“记忆”并持续进行正交分裂时,正交分裂才可以显著影响最终的细胞拓扑结构分布。在突变上皮组织中,研究结果表明,只有当边界细胞张力增大并结合不同的细胞增值速率时才可以重现实验观测的细胞拓扑结构分布偏移。其次,本论文研究了果蝇翅膀在发育过程中组织延展的调节机制。研究结果显示,在果蝇发育至成虫15-24小时期间,有向分裂、有向受力、和细胞体积减小共同调节组织延展,但它们作用不同。有向分裂和有向受力在组织延展过程中充当有向信号,引导组织沿PD轴延展。此外,本研究首次发现增殖过程中细胞体积减小对组织延展的全新调控机制。细胞体积减小本身不能引导组织延展,因为它不具有任何方向信息。然而,当与有向信号相结合(如细胞有向分裂和有向受力等),细胞体积减小可以显著促进组织延展的程度。最后,本论文研究了肿瘤侵润的力学作用机制。研究结果显示,当癌细胞与胞外基质的粘连力增强,并且与肿瘤细胞的粘连力降低时,肿瘤发生明显的侵润性行为。胞外基质细胞刚度增加时,会促进已发生侵润的肿瘤细胞进一步移动扩散。当然,胞外基质力学特性影响肿瘤侵润组织形态的前提是肿瘤组织本身已具有侵润能力。此外,胞外基质细胞刚度的增加还可以影响侵润性肿瘤细胞形状,使得癌细胞伸长,具有更高的灵活性和迁移能力。综上所述,本论文应用二维细胞模型,研究了不同上皮系统中细胞和组织形态发生发展的调节机制。首先,在增殖上皮组织的细胞拓扑结构的调节机制研究中,本论文首次提出了细胞分裂面在形成正常增殖上皮组织中不同物种间细胞多边形比率差异性的调控作用,首次提出并模拟验证了边界力学变化引起突变上皮组织中边界增殖细胞拓扑结构分布发生偏移的假说。其次,在简单上皮系统果蝇翅膀的形态延展机制研究中,本论文首次定量研究了有向分裂和有向受力作为有向信号引导果蝇翅膀延展的作用,并且首次发现细胞体积减小在果蝇翅膀形态延展中的关键调控作用。最后,在复杂上皮系统肿瘤侵润的力学调控机制研究中,本论文首次发现了胞外基质力学性能变化对肿瘤侵润的调控作用,并发现胞外基质力学性能改变可以反过来影响侵润性肿瘤细胞的形状。这些研究结果在临床治疗中具有重要指导意义。
[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.
【学位授予单位】：上海交通大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R730.2

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