A Microengineered Brain-Chip to Model Neuroinflammation in Humans

Species differences in the brain and the blood-brain barrier (BBB) biology hamper the translation from animal models to humans and impede the development of specific therapeutics for brain diseases. Here we present a human Brain-Chip engineered to recapitulate critical aspects of the complex brain c...

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Bibliographic Details
Published inbioRxiv
Main Authors Pediaditakis, Iosif, Kodella, Konstantia R, Manatakis, Dimitris V, Le, Christopher Y, Barthakur, Sonalee, Sorets, Alexander, Gravanis, Achille, Ewart, Lorna, Rubin, Lee L, Manolakos, Elias S, Hinojosa, Chris D, Karalis, Katia
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 15.03.2022
Subjects
Animal models
Blood-brain barrier
Cell culture
Cell interactions
Drug development
Inflammation
Membrane permeability
Mimicry
Neuronal-glial interactions
Perfusion
Pericytes
Permeability
Tumor necrosis factor-α
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Summary:Species differences in the brain and the blood-brain barrier (BBB) biology hamper the translation from animal models to humans and impede the development of specific therapeutics for brain diseases. Here we present a human Brain-Chip engineered to recapitulate critical aspects of the complex brain cell-cell interactions that mediate neuroinflammation development. Our human organotypic microphysiological system (MPS) includes endothelial-like cells, pericytes, glia, and cortical neurons and maintains BBB permeability at in vivo relevant levels, providing a significant improvement in complexity and clinical mimicry compared to previous MPS models. This is the first report of a Brain-Chip with an RNA expression profile close to that of the adult human cortex and that demonstrates advantages over Transwell culture. Through perfusion of TNF-α, we recreated key inflammatory features, such as glia activation, the release of proinflammatory cytokines, and increased barrier permeability. Our model may provide a reliable tool for mechanistic studies in neuron-glial interactions and dysregulation of BBB function during neuroinflammation. Competing Interest Statement I.P., K.R.K., D.V.M., C.Y.L, S.B., A.S., L.E., C.D.H., and K.K. are current or former employees of Emulate, Inc and may hold equity interests in Emulate, Inc. All other authors declare no competing interests.
DOI:10.1101/2022.03.11.484005