Abstract
The blood-brain barrier (BBB) constitutes the interface between the blood and the brain tissue. Its primary function is to maintain the tightly controlled microenvironment of the brain. Models of the BBB are useful for studying the development and maintenance of the BBB as well as diseases affecting it. Furthermore, BBB models are important tools in drug development and support the evaluation of the brain-penetrating properties of novel drug molecules. Currently used in vitro models of the BBB include immortalized brain endothelial cell lines and primary brain endothelial cells of human and animal origin. Unfortunately, many cell lines and primary cells do not recreate physiological restriction of transport in vitro. Human-induced pluripotent stem cell (iPSC)-derived brain endothelial cells have proven a promising alternative source of brain endothelial-like cells that replicate tight cell layers with low paracellular permeability. Given the possibility to generate large amounts of human iPSC-derived brain endothelial cells they are a feasible alternative when modelling the BBB in vitro. iPSC-derived brain endothelial cells form tight cell layers in vitro and their barrier properties can be enhanced through coculture with other cell types of the BBB. Currently, many different models of the BBB using iPSC-derived cells are under evaluation to study BBB formation, maintenance, disruption, drug transport and diseases affecting the BBB. This review summarizes important functions of the BBB and current efforts to create iPSC-derived BBB models in both static and dynamic conditions. In addition, it highlights key model requirements and remaining challenges for human iPSC-derived BBB models in vitro.
Highlights
The blood-brain barrier (BBB) constitutes the interface between the blood and the brain tissue
Isolated primary brain endothelial cells rapidly lose their BBB properties when cultured in vitro (Urich et al, 2012), it is plausible that the BBB properties are not intrinsic to the brain endothelial cells but rather depend on the specific microenvironment that all the components of the NVU create together
Inter-cellular junctions between the endothelial cells at the BBB are made up of TJs and adherens junctions (AJs), in addition, cluster of differentiation 31 (CD31) protein is highly expressed and its connections contribute to cell-cell adhesion (Bauer et al, 2014; Vanlandewijck et al, 2018)
Summary
The blood-brain barrier (BBB) is the interface between the blood and the brain tissue. The structure and function of the BBB has been reviewed elsewhere, for detailed reviews see references 1 and 2 by Obermeier et al and Abbott et al The brain endothelial cells control the permeability of the barrier. Astrocytic end-feet are in contact with the basal membrane This unit of astrocytes, pericytes, basal membrane and endothelial cells is often referred to as the neurovascular unit (NVU, Fig. 1) (Iadecola, 2017; Obermeier et al, 2013). Together these components make up the BBB and govern its development, maintenance and function. To be able to predict and study the human BBB a human model is highly preferable
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