title: An integrative microfluidically supported in vitro model of an endothelial barrier combined with cortical spheroids simulates effects of neuroinflammation in neocortex development.
abstract: The development of therapeutic substances to treat diseases of the central nervous system is hampered by the tightness and selectivity of the blood-brain barrier. Moreover, testing of potential drugs is time-consuming and cost-intensive. Here, we established a new microfluidically supported, biochip-based model of the brain endothelial barrier in combination with brain cortical spheroids suitable to detect effects of neuroinflammation upon disruption of the endothelial layer in response to inflammatory signals. Unilateral perfusion of the endothelial cell layer with a cytokine mix comprising tumor necrosis factor, IL-1β, IFNγ, and lipopolysaccharide resulted in a loss of endothelial von Willebrand factor and VE-cadherin expression accompanied with an increased leakage of the endothelial layer and diminished endothelial cell viability. In addition, cytokine treatment caused a loss of neocortex differentiation markers Tbr1, Tbr2, and Pax6 in the cortical spheroids concomitant with reduced cell viability and spheroid integrity. From these observations, we conclude that our endothelial barrier/cortex model is suitable to specifically reflect cytokine-induced effects on barrier integrity and to uncover damage and impairment of cortical tissue development and viability. With all its limitations, the model represents a novel tool to study cross-communication between the brain endothelial barrier and underlying cortical tissue that can be utilized for toxicity and drug screening studies focusing on inflammation and neocortex formation.
authors.affiliation: Institute of Biochemistry II, Jena University Hospital, Jena, Germany and Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
authors.forename: Martin
authors.initials: M
authors.lastname: Raasch
authors.affiliation: Institute of Biochemistry II, Jena University Hospital, Jena, Germany and Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
authors.forename: Knut
authors.initials: K
authors.lastname: Rennert
authors.affiliation: microfluidic ChipShop GmbH , Jena, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Jahn
authors.affiliation: microfluidic ChipShop GmbH , Jena, Germany.
authors.forename: Claudia
authors.identifier: 0000-0003-4547-9097
authors.initials: C
authors.lastname: Gärtner
authors.affiliation: Federal Institute for Risk Assessment (BfR), German Centre for the Protection of Laboratory Animals (Bf3R), Max-Dohrn-Str. 8-10, 10589 Berlin, Germany and Department of Clinical Pharmacology and Toxicology, Charité–Universitätsmedizin Berlin, Berlin, Germany
authors.forename: Gilbert
authors.initials: G
authors.lastname: Schönfelder
authors.affiliation: Institute of Biochemistry II, Jena University Hospital, Jena, Germany
authors.forename: Otmar
authors.initials: O
authors.lastname: Huber
authors.affiliation: Federal Institute for Risk Assessment (BfR), German Centre for the Protection of Laboratory Animals (Bf3R) , Max-Dohrn-Str. 8-10, 10589 Berlin, Germany.
authors.forename: Andrea E M
authors.initials: AE
authors.lastname: Seiler
authors.affiliation: Institute of Biochemistry II, Jena University Hospital, Jena, Germany and Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
authors.forename: Alexander S
authors.identifier: 0000-0002-5687-2444
authors.initials: AS
authors.lastname: Mosig