Computational modeling of cell behavior in three-dimensional matrices
- Autores: Seyed Jamaleddin Mousavi
- Directores de la Tesis: Doweidar Taky el Din Mohamed Hamdy Doweidar (dir. tes.)
- Lectura: En la Universidad de Zaragoza ( España ) en 2015
- Idioma: español
- Tribunal Calificador de la Tesis: Guillermo Hauke Bernardos (presid.), Gloria Gallego Ferrer (secret.), Salah Ramtani (voc.)
- Materias:
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- Resumen
Cell migration, differentiation, proliferation and morphology are essential processes in many physiological and pathological processes ranging from wound healing to malignant diseases such as cancer. Individual cell migration positions cells in tissues during morphogenesis and cancer, or allows them to pass through the tissue, as seen by immune cells. On the other hand, collective cell migration, such as neural crest, vasculature and many epithelial cells migration, is another fundamental form of cell translocation which may relatively differ from individual cell migration. During cell migration, amoeboid movement causes frequent changes in cell shape due to the extension of protrusions in the cell front and retraction of cell rear. Regulation of intracellular mechanics and cell's physical interaction with its substrate rely on control of cell shape during cell migration. Hence, it is of central importance to understand this process in many biological processes ranging from morphogenesis to metastatic cancer cells.
Cell migration is governed by a complex network of signal transduction pathways. It has been demonstrated that, in addition to mechanotaxis, cell migration can be also directed by chemical, thermal and/or electrical stimuli. To achieve productive cell migration, each signaling passway may be temporally and spatially effective in particular regions of the substrate in which the cell migrates. Besides, experimental observations confirm that cells may undergo differentiation and/or proliferation due to mechano-sensing process. For instance, mesenchymal stem cells (MSCs) are susceptible to differentiate into different cell types such as neuroblast, chondrocyte, osteoblast and many others within substrates mimicking the stiffness of their native Extracellular matrix (ECM).
In these concepts, numerical methods can effectively assist to better understand the physical mechanism behind different aspects of cell behavior such as singular or collective cell migration, cell morphological changes, cell differentiation and proliferation. However, they are also helpful tool to design more efficient experimental setups. Therefore, through the present dissertation, the main objective is to develop a numerical model that considers different features of single and collective cell behavior in existence of different stimuli in their micro-environment. Guided by experiential observations, the cell translocation is modeled by the equilibrium of effective forces on cell body such as traction, protrusion, electrostatic and drag forces, assuming that the cell traction forces are regulated by the cell internal deformations. To do so, the finite element discrete methodology is employed in which the cell is represented by a group of finite elements following two different strategies; a constant spherical cell shape and a free mood cell shape.
Our findings, which are qualitatively consistent with well-known related experimental observations, indicate that the cell migrates persistently towards stiffer or more fixed regions in its neighbors. Any change in substrate stiffness and/or in the boundary conditions may affect the path tracked by the cell and the cell final location. During cell migration within a substrate with stiffness gradient, nodal traction forces increase while net traction force as well as cell velocity decrease. In very soft or very stiff substrates, generated net traction forces may not be strong enough to enable the cell anchors or penetrates further into the substrate. Besides, during superficial cell migration on a substrate with restricted lower layer, the cell tendency is to migrate towards lower depth locations of the substrate.
On the other hand, when another activation signal is added to the substrate, the overall cell behavior changes. For instance, in the presence of chemotaxis and/or thermotaxis the cell final location is quite sensitive to the imposed effective factors. Despite of the free boundary surface, in the presence of thermotaxis and/or chemotaxis, the cell final location displaces towards higher temperature and/or chemical concentration. Although the effect of these cues is negligible on the cell local velocity, these signals remarkably affect the reorientation of the cell and reduce its random motility. Moreover, it is well known that a typical cell may migrate towards the cathode pole in the presence of exogenous electric field (EF). Amplification of the EF can accelerate this phenomenon and causes the cell to move more directionally. Electrotaxis has a dominant guidance role in directing cell migration compared to other stimuli.
During collective cell migration, the associated cell behavior is relatively different. For instance, cells tend to create small slugs within the substrate and then these slugs aggregate in the middle or end of the substrate depending on substrate characteristics (substrate stiffness and boundary conditions). In addition, interaction between cells inside the substrate delays their movement towards stiffer regions. This is because the signal coming from their inter-stretched region induces the cells to move towards each other and maintain in contact. This interaction changes the profile of average net traction force and average velocity of the cells. It is noteworthy to mention that adding any new stimulus into the substrate displace cell aggregation centroid towards this new cue. However, high electrical field strength can even cause the cell slug to be flatten near the cathode pole.
Similar to cell migration, cell shape can be regulated by cell internal deformation which is coupled with the mechanical characteristics of the cell micro-environment. A resident cell within an unconstrained soft (several kPa) or hard (greater than hundred kPa) substrate is unable to adhere or penetrate into its substrate and keeps a spherical shape. When the substrate stiffness is about tens of kPa (intermediate and rigid substrates), the cell can adequately adhere to the substrate, increasing the traction forces, the cell elongation and Cellular Morphology Index (CMI). Maximum cell elongation occurs in the middle of a constrained rigid substrate, which decreases when the cell approaches a constrained surface. It can be concluded that the higher the net traction force, the greater the cell elongation and the larger the cell membrane area (CMI). Besides, the overall cell shape (cell elongation and CMI) may be changed by activation of other stimuli. For instance, by adding chemotaxis, thermotaxis and/or electrotaxis to the cell substrate, average cell elongation and CMI increases. However, the average cell elongation and CMI are maximum in the presence of electrotaxis which confirm dominant role of electrotaxis.
In addition, using the present model, we can quantify cell differentiation and proliferation due to mechanotaxis. MSC differentiates into neurogenic, chondrogenic or osteogenic lineage specifications within soft (0.1-1 kPa), intermediate (20-25 kPa) or relatively hard (30-45 kPa) substrates, respectively. When a MSC differentiate to a compatible phenotype, the average net traction force depends on the substrate stiffness in such a way that it might increase in intermediate and hard substrates but it would reduce in a soft matrix. However, the average net traction force considerably increases at the instant of cell proliferation due to cell-cell interaction.
In addition, cell differentiation and proliferation can be accelerated by increasing substrate the stiffness within the relative range.
