Modeling The Morphogenesis Of Epithelial Tissues And Its Applications In Tissue Growth And Tumor Invation

Epithelia are composed of tightly adherent epithelial cells and stromal cells that line on the surfaces of metazoans. They serve as protective barriers from the external physical and chemical stimuli. Epithelial morphogenesis plays important roles in embryonic development, tissue formation, and disease development, especially in cancer. About 90% of human cancers originate from mutated epithelial cells. Therefore, studying epithelial morphogenesis can help us understand important biological processes such as organ development and tumor invasion. In this research, the previously developed two-dimensional dynamic cellular model in Liang’s group was applied to study epithelial morphogenesis in different biological systems, including the regulating mechanism of cell topology in proliferating epithelia, tissue elongation in Drosophila wing, and the mechanics of tumor invasion.The two-dimensional cellular model used to study epithelial morphogenesis. This model describes both the geometric and the mechanical properties of cells. In addition, it incorporates both the properties of individual cells(such as growth rate, division rate, the orientation of cell division, the concentration of intracellular proteins) and the interplay among multiple cells(such as the interactions between neighboring cells, topological feedback). Furthermore, this model describes the topological changes that may occur during the dynamic tissue growth. Simulation results of epithelial proliferation with the cellular model showed regular cell shapes, which accorded well with experimental observations. Development of the cellular model provides us an effective platform to study epithelial morphogenesis.Firstly, the regulating mechanism of cell topology in proliferating epithelia was studied. In epithelial tissues, with cell division and cell rearrangement, the cellular model generated the conserved topological distributions observed in nature. With different division planes(the largest side and the orthogonal division planes), different frequencies of hexagonal cells among different species were generated. Between these two division planes, the largest side divided randomly, while the orthogonal one divided with certainty. Cell topology could be affected only when cells had ―memory‖ and continuously divided with the orthogonal division plane. In mutated epithelial tissues, the results showed that when the tension on the boundary increased, combining with different cell proliferation rate, the topological shift observed in experiments could be simulated.Secondly, the regulating mechanism of tissue elongation in Drosophila wing was studied. Simulation results showed that, oriented cell divisions, oriented mechanical forces, and reduced cell size could all mediate tissue elongation between 15 to 24 hours after puparium formation during pupal development, but they functioned differently. Oriented cell divisions and oriented mechanical forces acted as directional cues during PD-axis elongation. In addition, a novel hypothesis in this research is that reduced cell size may significantly promote tissue elongation. It was found that reduced cell size alone could not drive tissue elongation. However, when combined with directional cues, such as oriented cell divisions or oriented mechanical forces, reduced cell size could significantly enhance tissue elongation in Drosophila wing.Finally, the mechanics of tumor invasion was also studied. Simulation results showed that, decreased adhesion among tumor cells and increased adhesion to extracellular matrix(ECM) resulted in aggressively invasive tumor behaviors. Increase of the degradation and stiffness of ECM could promote tumor invasion only when the cell-cell adhesion relationship was satisfied for tumor invasion. Certainly, the invasive ability of tumor was the premise of ensuring the mechanics of ECM could influence tumor invasion. In addition, increase of the degradation and stiffness of ECM could also affect the shapes of invasive cancer cells, generating elongated cell shapes with higher motility to migrate.In summary, a two-dimensional cellular model was applied to study the regulating mechanism of epithelial morphogenesis in different biological systems. Firstly, in the study of the regulating mechanism of cell topology in proliferating epithelia, the controlling mechanism of the orientation of division plane in the formation of different polygonal frequency between species was shown, and it was first proposed and verified that mechanical forces induced the topological shift in mutated proliferating epithelia. Then in the study of the elongation of Drosophila wing, a simple epithelial tissue, quantitatively analyses were performed to investigate the function of oriented cell divisions and oriented mechanical forces as directional cues. It has shown the key regulating function of reduced cell size in tissue elongation. Finally, in the study of the mechanics of tumor invasion, a complex epithelial system with different cell types, the mechanics of extracellular matrix and cell-cell adhesion in tumor invasion was illustrated. It also showed that changes in ECM might affect the shape of invasive tumor cells. These results provide significant insight into clinical treatment.