Elevated interstitial flow in the cerebrospinal fluid microenvironment accelerates glioblastoma cell migration on a microfluidic chip.

Abstract

Glioblastoma is one of the most malignant tumors in the world, but the development of its therapies remains limited. Herein, a microfluidic chip that mimics the cerebrospinal fluid (CSF) circulation microenvironment is proposed to study the migration characteristics of glioblastoma U87-MG cells and U251 cells in complex environments where glioblastoma coexists with diseases that elevate CSF levels. In the presence of interstitial flow (IF), changing both cell densities and the cellular environment results in increased cell motility, including an increase in the number of migrating cells, the mean displacement of the top 30% fastest-moving cells, and the overall mean displacement. Then, through dynamic migration characterization analysis, it was found that IF enhances cell velocity and speed. Importantly, cells exposed to IF tend to migrate in directions with smaller angles of deviation from the opposite direction of IF. Finally, cytoskeleton inhibitors and decreased expressions of focal adhesion proteins, such as cytochalasin D, FAK inhibitors (VS-6063 and PF-573228), and FAK siRNA, were both proved to decrease the cells' response to IF. This work not only demonstrates the effect of IF on glioblastoma cell migration, but also indicates the reliability of microfluidic chips for modeling complex physiological environments, which is expected to be further developed for drug screening.