Logo Logo
Help
Contact
Switch language to German
Towards cellular hydrodynamics: collective migration in artificial microstructures
Towards cellular hydrodynamics: collective migration in artificial microstructures
The collective migration of cells governs many biological processes, including embryonic development, wound healing and cancer progression. Observed phenomena are not simply the sum of the individual motion of many isolated cells, but rather emerge as a consequence of their interactions. The movements in epithelial cell sheets display rich phenomenology, such as the occurrence of vortices spanning several cell diameters and the transition from fluid-like behavior at low densities to glass-like behavior at high densities. In this thesis, collective invasion of epithelial cell sheets into microchannels was studied on a phenomenological level within the scope of theoretical approaches to active fluids. In a first project, the motion profile of a cell layer in straight channels was investigated using single cell tracking and particle image velocimetry (PIV) on timelapse microscopy data. A defined plug-flow like velocity profile was observed across the channels. The cell density profile is well-described by the Fisher-Kolmogorov reaction-diffusion equation, which includes active migration and the contribution of proliferation. This study revealed a change in the short scale noise behavior in the presence of this global invasion into a channel. For a closer look at the system’s proliferation component, the effect of an underlying global migration direction on the orientation of the cells’ division axes was examined. We found strong alignment of the axes’ orientation with the imposed movement direction. Specifically, the strongest correlations were observed between the orientation of the cells’ division axes and the local strain rate tensor’s main axis. This is in agreement with the notion that stresses in the migrating cell sheet orient the cell divisions. Expanding the assay of invasion into straight channels, we introduced a constriction, which the cell sheet needs to pass through in order to progress. A plateau of low velocities was observed in the region ahead of the constriction, which was attributed to an increase in local cell density accompanied by jamming. These results were compared to an active isotropic-nematic mixture model. The suitability of this model to describe this assay could be ruled out, however, as it showed qualitatively very different behavior than the experiments. Finally, the frequency of topological nearest-neighbor T1 transitions within a cell sheet was investigated in minimal model systems. In order to study the smallest possible fundamental unit for such transitions, groups of four cells were confined to cloverleaf patterns, which could be shown to inhibit the onset of collective rotation states. Results showed that T1 transitions occurred more frequently for groups of cells with a lower average length of the cell-cell junction that shrinks in the process of this transition. These results are consistent with the notion that the energy barrier which needs to be overcome by the cells in order to perform this transition, scales with the original length of the shrinking junction. Taken together, the results of this thesis contribute to a better understanding of the flow fields for collective cell migration processes in confined geometries. In addition to the insights the phenomenological observations in this work could provide directly, they will also continue to prove useful as a standard for validating detailed theoretical models.
Collective Cell Migration
Zorn, Matthias
2018
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Zorn, Matthias (2018): Towards cellular hydrodynamics: collective migration in artificial microstructures. Dissertation, LMU München: Faculty of Physics
[img]
Preview
PDF
Zorn_Matthias_L.pdf

21MB

Abstract

The collective migration of cells governs many biological processes, including embryonic development, wound healing and cancer progression. Observed phenomena are not simply the sum of the individual motion of many isolated cells, but rather emerge as a consequence of their interactions. The movements in epithelial cell sheets display rich phenomenology, such as the occurrence of vortices spanning several cell diameters and the transition from fluid-like behavior at low densities to glass-like behavior at high densities. In this thesis, collective invasion of epithelial cell sheets into microchannels was studied on a phenomenological level within the scope of theoretical approaches to active fluids. In a first project, the motion profile of a cell layer in straight channels was investigated using single cell tracking and particle image velocimetry (PIV) on timelapse microscopy data. A defined plug-flow like velocity profile was observed across the channels. The cell density profile is well-described by the Fisher-Kolmogorov reaction-diffusion equation, which includes active migration and the contribution of proliferation. This study revealed a change in the short scale noise behavior in the presence of this global invasion into a channel. For a closer look at the system’s proliferation component, the effect of an underlying global migration direction on the orientation of the cells’ division axes was examined. We found strong alignment of the axes’ orientation with the imposed movement direction. Specifically, the strongest correlations were observed between the orientation of the cells’ division axes and the local strain rate tensor’s main axis. This is in agreement with the notion that stresses in the migrating cell sheet orient the cell divisions. Expanding the assay of invasion into straight channels, we introduced a constriction, which the cell sheet needs to pass through in order to progress. A plateau of low velocities was observed in the region ahead of the constriction, which was attributed to an increase in local cell density accompanied by jamming. These results were compared to an active isotropic-nematic mixture model. The suitability of this model to describe this assay could be ruled out, however, as it showed qualitatively very different behavior than the experiments. Finally, the frequency of topological nearest-neighbor T1 transitions within a cell sheet was investigated in minimal model systems. In order to study the smallest possible fundamental unit for such transitions, groups of four cells were confined to cloverleaf patterns, which could be shown to inhibit the onset of collective rotation states. Results showed that T1 transitions occurred more frequently for groups of cells with a lower average length of the cell-cell junction that shrinks in the process of this transition. These results are consistent with the notion that the energy barrier which needs to be overcome by the cells in order to perform this transition, scales with the original length of the shrinking junction. Taken together, the results of this thesis contribute to a better understanding of the flow fields for collective cell migration processes in confined geometries. In addition to the insights the phenomenological observations in this work could provide directly, they will also continue to prove useful as a standard for validating detailed theoretical models.