A 3D Model of the Human Blood Brain Barrier

Researchers at Vanderbilt University have developed a functional 3D in vitro blood-brain barrier model constructed from induced pluripotent stem cell (iPSC)-derived human brain microvascular endothelial cells (BMECs) that mimics in vivo human properties of brain microvasculature and the blood brain barrier and can be used to study diseases and develop therapeutics

HUMAN HEALTH ISSUE

The brain endothelium plays an important role in the healthy functioning of the brain and central nervous system. Its dysfunction is associated with many neurological conditions and even some nonneuronal disorders, such as diabetes. The lack of a good model for studying this tissue impedes our ability to understand basic neurological mechanisms and to identify novel therapeutic targets.

ANIMAL FREE SCIENCE INNOVATION POTENTIAL

Researchers differentiated induced pluripotent stem cells (iPSC) into human brain microvascular endothelial cells and cultured them in 3D hydrogel channels at tissue scale in what they describe as a relatively simple fabrication and implementation process. The resulting model of the neurovascular unit is stable long-term and mimics both active and passive features of the blood brain barrier.

SCIENTIFIC ABSTRACT

There is a profound need for functional, biomimetic in vitro tissue constructs of the human blood-brain barrier and neurovascular unit (NVU) to model diseases and identify therapeutic interventions. Here, we show that induced pluripotent stem cell (iPSC)-derived human brain microvascular endothelial cells (BMECs) exhibit robust barrier functionality when cultured in 3D channels within gelatin hydrogels. We determined that BMECs cultured in 3D under perfusion conditions were 10–100 times less permeable to sodium fluorescein, 3 kDa dextran, and albumin relative to human umbilical vein endothelial cell and human dermal microvascular endothelial cell controls, and the BMECs maintained barrier function for up to 21 days. Analysis of cell-cell junctions revealed expression patterns supporting barrier formation. Finally, efflux transporter activity was maintained over 3 weeks of perfused culture. Taken together, this work lays the foundation for development of a representative 3D in vitro model of the human NVU constructed from iPSCs.

Source: Faley SL, Neal EH, Wang JX, et al. iPSC-derived brain endothelium exhibits stable, long-term barrier function in perfused hydrogel scaffolds. Stem Cell Reports. 2019;12:474-487https://doi.org/10.1016/j.stemcr.2019.01.009