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

Raleigh M. Linville, Jackson G. DeStefano, Matt B. Sklar, Chengyan Chu, Piotr Walczak, Peter C. Searson

Research output: Contribution to journalArticle

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 that tissue-engineered BBB models can provide insight into the mechanisms of BBBO and hence improve the reproducibility of hyperosmotic therapies for treatment of CNS disease.

Original languageEnglish (US)
JournalJournal of Cerebral Blood Flow and Metabolism
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Microvessels
Mannitol
Brain
Central Nervous System Diseases
Permeability
Therapeutics
Intra Arterial Infusions
Fibroblast Growth Factor 2
Cell Communication
Stem Cells
Endothelial Cells
In Vitro Techniques

Keywords

  • Blood–brain barrier
  • hyperosmotic blood–brain barrier opening
  • mannitol
  • microvessels
  • three-dimensional in vitro models

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

Cite this

Modeling hyperosmotic blood–brain barrier opening within human tissue-engineered in vitro brain microvessels. / Linville, Raleigh M.; DeStefano, Jackson G.; Sklar, Matt B.; Chu, Chengyan; Walczak, Piotr; Searson, Peter C.

In: Journal of Cerebral Blood Flow and Metabolism, 01.01.2019.

Research output: Contribution to journalArticle

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