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Computational modeling of the neurovascular unit to predict microglia mediated effects on blood-brain barrier formation (Teratology Society Annual Meeting)
Citation:
Zurlinden, T., K. Saili, R. Spencer, N. Baker, AND T. Knudsen. Computational modeling of the neurovascular unit to predict microglia mediated effects on blood-brain barrier formation (Teratology Society Annual Meeting). Presented at Teratology Society Annual Meeting, Denver, Colorado, June 24 - 28, 2017.
Impact/Purpose:
Abstract for presentation at Teratology Society annual meeting to address the complexities of chemical exposure on the developing BBB, a cell agent based model (ABM) was developed to predict the formation of the NVU with specific focus on the interaction between invading endothelial cells and microglia.
Description:
Development of a functional blood-brain barrier (BBB) is a complex process regulated by multiple cell types at different developmental stages. One important aspect of the developing neurovascular unit (NVU) involves interaction between invading endothelial cells, neuroprogenitor cells comprising the subventricular plexus, and microglia, the resident macrophages of the central nervous system (CNS). Microglia serve as an important mediator between neurologic and immunologic function and dysregulation of these cells during development is hypothesized to disrupt BBB formation via decreased vessel branching and compromised vessel stabilization. To address the complexities of chemical exposure on the developing BBB, a cell agent based model (ABM) was developed to predict the formation of the NVU with specific focus on the interaction between invading endothelial cells and microglia. Building upon a previous model of vasculogenesis, the current ABM characterizes the complex interaction between microglia and invading endothelial cells by incorporating multiple signaling pathways (Notch/dll4, CSF-1, VEGF-A, VEGF-C, sFlt1) in a biological framework. Molecular targets in the ABM were linked to signatures of neurovascular disruption through in vitro assay results in EPA’s ToxCast high throughput screening dataset. Specifically, colony stimulating factor 1 receptor (CSF-1R) served as a marker of microglia abundance in the developing neuroepithelium. Concentration response effects using the NVS_ENZ_hCSF1R assay in ToxCast were translated to chemical-specific effects on microglia abundance. ABM simulations of chemical-induced reduction in microglia resulted in a compromised NVU vasculature represented by decreased blood vessel branching and sprouting. Microglia interactions with the invading endothelial cells represent an important aspect of the computational NVU model (cNVU). Development of the cNVU will facilitate predictions of perturbations to the complex biology of the developing NVU from available in vitro data. [This abstract may not reflect US EPA policy].