The Influence of Hyaluronic Acid and Glioblastoma Cell Coculture on the Formation of Endothelial Cell Networks in Gelatin Hydrogels

Glioblastoma (GBM) is the most common and deadly form of brain cancer. Interactions between GBM cells and vasculature in vivo contribute to poor clinical outcomes, with GBM-induced vessel co-option, regression, and subsequent angiogenesis strongly influencing GBM invasion. Here, elements of the GBM perivascular niche are incorporated into a methacrylamide-functionalized gelatin hydrogel as a means to examine GBM–vessel interactions. The complexity of 3D endothelial cell networks formed from human umbilical vein endothelial cells and normal human lung fibroblasts as a function of hydrogel properties and vascular endothelial growth factor (VEGF) presentation is presented. While overall length and branching of the endothelial cell networks decrease with increasing hydrogel stiffness and incorporation of brain-mimetic hyaluronic acid, it can be separately altered by changing the vascular cell seeding density. It is shown that covalent incorporation of VEGF supports network formation as robustly as continuously available soluble VEGF. The impact of U87-MG GBM cells on the endothelial cell networks is subsequently investigated. GBM cells localize in proximity to the endothelial cell networks and hasten network regression in vitro. Together, this in vitro platform recapitulates the close association between GBM cells and vessel structures as well as elements of vessel co-option and regression preceding angiogenesis in vivo.

The glioblastoma perivascular niche is incorporated into a gelatin hydrogel via coculture of endothelial, stromal, and glioblastoma cells. Endothelial network complexity can be manipulated through hydrogel stiffness and covalent immobilization of brain-mimetic hyaluronic acid and vascular endothelial growth factor into the hydrogel network. Glioblastoma cells associate closely with endothelial cell networks and promote processes similar to vessel co-option and regression seen in vivo.

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