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Kaushik, Gaurav; Gupta, Kartik; Harms, Victoria; Torr, Elizabeth; Evans, Jonathan; Johnson, Hunter J.; Soref, Cheryl; Acevedo‐Acevedo, Suehelay; Antosiewicz‐Bourget, Jessica; Mamott, Daniel; Uhl, Peyton; Johnson, Brian P.; Palecek, Sean P.; Beebe, David J.; Thomson, James A.; Daly, William T.; Murphy, William L.
Advanced healthcare materials, 08/2020, Letnik: 9, Številka: 16Journal Article
There is a vital need to develop in vitro models of the developing human brain to recapitulate the biological effects that toxic compounds have on the brain. To model perineural vascular plexus (PNVP) in vitro, which is a key stage in embryonic development, human embryonic stem cells (hESC)‐derived endothelial cells (ECs), neural progenitor cells, and microglia (MG) with primary pericytes (PCs) in synthetic hydrogels in a custom‐designed microfluidics device are cocultured. The formation of a vascular plexus that includes networks of ECs (CD31+, VE‐cadherin+), MG (IBA1+), and PCs (PDGFRβ+), and an overlying neuronal layer that includes differentiated neuronal cells (βIII Tubulin+, GFAP+) and radial glia (Nestin+, Notch2NL+), are characterized. Increased brain‐derived neurotrophic factor secretion and differential metabolite secretion by the vascular plexus and the neuronal cells over time are consistent with PNVP functionality. Multiple concentrations of developmental toxicants (teratogens, microglial disruptor, and vascular network disruptors) significantly reduce the migration of ECs and MG toward the neuronal layer, inhibit formation of the vascular network, and decrease vascular endothelial growth factor A (VEGFA) secretion. By quantifying 3D cell migration, metabolic activity, vascular network disruption, and cytotoxicity, the PNVP model may be a useful tool to make physiologically relevant predictions of developmental toxicity. Current models of in vitro brain development fail to mimic mechanisms in vivo, partly as they use animal‐derived matrices. The current study incorporates differentiated cell lines in a fabricated synthetic hydrogel in a microfluidics plate to recapitulate perineural vascular plexus in vivo. By analyzing endpoints such as growth factors, metabolites and 3D cell migration, this model predicts acute toxicity mechanisms.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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