Interstitial Fluid Flow Magnitude and Its Effects on Glioblastoma Invasion


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Virginia Tech


Fluid flow is a complex and dynamic process in the brain, taking place at the macro- and microscopic level. Interstitial fluid in particular flows throughout the interstitial spaces within the tissue, interacting with cells and the extracellular matrix. We are coming to find that this interstitial fluid flow plays an important role in both homeostatic and pathologic conditions. It helps to transport chemokines and other molecules such as extracellular vesicles within the environment, clear waste from the brain, and provide biophysical cues to cells. When this flow is disrupted however, such as in glioblastoma or Alzheimer's disease, profound events can occur, for example the build-up of plaques or an increase in tumor cell invasion. While there has recently been an up-tick in interstitial fluid flow research, there is surprisingly little known about its exact nature within the interstitial space and its effects on brain pathology such as glioblastoma. In particular, ways to manipulate and measure brain IFF magnitude at the cellular level are lacking. In this dissertation, a set of tools is created and used to explore the role that interstitial fluid flow magnitude plays in the brain through the lens of glioma invasion. We developed and implemented a flow device that is used in conjunction with an established in vitro tissue culture insert assay to manipulate fluid flow rates through a 3D matrix of tumor cells. We showed that this flow device is biocompatible and accurately recreates flow rates that have been measured previously through the use of MRI. We quantified tumor cell invasion from several glioma cell lines using this device to show a nonlinear trend of invasion in response to increasing fluid flow magnitudes. In addition, we developed a computational model to explore one potential mechanism that fluid flow magnitude might be modulating: autologous chemotaxis. Through this model we showed that increased flow magnitudes such as those seen in gliomas cause an increase in the distribution of the chemokine gradient around a cell of interest, that the morphology of the cell is important to this gradient formation, that temporal effects should not be overlooked, and that within the tumor environment, a minimum distance is required for the invading cell to develop this gradient. Finally, we developed a novel in vivo surgical technique that allows for the manipulation and measurement of interstitial fluid flow within the brain through simultaneous multiphoton imaging. We showed that this technique can be used to modulate interstitial fluid flow, as a mechanism by which to label cells of interest, and as a means to implant and monitor glioma progression. Through these means we further characterize interstitial fluid flow in the brain, allowing for its manipulation and measurement, and examine the ability of increased interstitial fluid flow magnitudes to impact glioma invasion.



interstitial fluid, flow, magnitude, glioblastoma, invasion, device, models, intravital