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.
Controlled delivery of cytokines and growth factors has been an area of intense research interest for molecular and cellular bioengineering, immunotherapy, and regenerative medicine. This study shows that primary human lung fibroblasts chemically induced to senescence (cell cycle arrest) can act as a living source to transiently produce factors essential for promoting vasculogenesis or angiogenesis, such as vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and interleukin 8 (IL‐8). Coculture of senescent fibroblasts with human umbilical vein endothelial cells in a fibrin gel demonstrate accelerated formation and maturation of microvessel networks in as early as three days. Unlike the usage of nonsenescent fibroblasts as the angiogenesis‐promoting cells, this approach eliminates drawbacks related to the overproliferation of fibroblasts and the subsequent disruption of tissue architecture, integrity, or function. Coculture of mouse pancreatic islets with senescent fibroblasts and endothelial cells in a gel matrix maintains the viability and function of islets ex vivo for up to five days. Applying senescent fibroblasts to wound repair in vivo leads to increased blood flow in a diabetic mouse model. Together, this work points to a new direction for modeling the delivery of cytokines and growth factors that promote microvascular tissue engineering and tissue repairs.
more » « less- NSF-PAR ID:
- 10460026
- Publisher / Repository:
- Wiley Blackwell (John Wiley & Sons)
- Date Published:
- Journal Name:
- Advanced Biosystems
- Volume:
- 3
- Issue:
- 8
- ISSN:
- 2366-7478
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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