Modeling hyperosmotic blood-brain barrier opening within human tissue-engineered in vitro brain microvessels.

Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism
Raleigh M LinvillePeter C Searson

Abstract

As the majority of therapeutic agents do not cross the blood-brain barrier (BBB), transient BBB opening (BBBO) is one strategy to enable delivery into the brain for effective treatment of CNS disease. Intra-arterial infusion of the hyperosmotic agent mannitol reversibly opens the BBB; however, widespread clinical use has been limited due to the variability in outcomes. The current model for mannitol-induced BBBO assumes a transient but homogeneous increase in permeability; however, the details are poorly understood. To elucidate the mechanism of hyperosmotic opening at the cellular level, we developed a tissue-engineered microvessel model using stem cell-derived human brain microvascular endothelial cells (BMECs) perturbed with clinically relevant mannitol doses. This model recapitulates physiological shear stress, barrier function, microvessel geometry, and cell-matrix interactions. Using live-cell imaging, we show that mannitol results in dose-dependent and spatially heterogeneous increases in paracellular permeability through the formation of transient focal leaks. Additionally, we find that the degree of BBB opening and subsequent recovery is modulated by treatment with basic fibroblast growth factor. These results show tha...Continue Reading

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Citations

Apr 24, 2020·Fluids and Barriers of the CNS·Michael J Workman, Clive N Svendsen
Dec 28, 2019·Micromachines·Christopher A HeshWilbur A Lam
Sep 8, 2020·Advanced Healthcare Materials·Joe Tien, Yoseph W Dance
Jul 17, 2020·Microvascular Research·Raleigh M LinvillePeter C Searson
Apr 10, 2021·Stem Cell Reports·Shane BrowneKevin E Healy
May 1, 2021·Micromachines·Tiffany CameronKaren C Cheung
May 8, 2021·Journal of Cellular Physiology·Karolina KriaučiūnaitėAugustas Pivoriūnas
Oct 12, 2021·Frontiers in Neuroscience·Jonathan M Fischell, Paul S Fishman

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Methods Mentioned

BETA
fluorescence imaging

Software Mentioned

ARRIVE
ImageJ

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