Human Induced Pluripotent Stem Cell-Derived Brain Endothelial Cells: Current Controversies

Abstract

Brain microvascular endothelial cells (BMECs) possess unique properties that are crucial for many functions of the blood-brain-barrier (BBB) including maintenance of brain homeostasis and regulation of interactions between the brain and immune system. The generation of a pure population of putative brain microvascular endothelial cells from human pluripotent stem cell sources (iBMECs) has been described to meet the need for reliable and reproducible brain endothelial cells in vitro. Human pluripotent stem cells (hPSCs), embryonic or induced, can be differentiated into large quantities of specialized cells in order to study development and model disease. These hPSC-derived iBMECs display endothelial-like properties, such as tube formation and low-density lipoprotein uptake, high transendothelial electrical resistance (TEER), and barrier-like efflux transporter activities. Over time, the de novo generation of an organotypic endothelial cell from hPSCs has aroused controversies. This perspective article highlights the developments made in the field of hPSC derived brain endothelial cells as well as where experimental data are lacking, and what concerns have emerged since their initial description.

Comparative studies between the murine immortalized brain endothelial cell line (bEnd.3) and induced pluripotent stem cell-derived human brain endothelial cells for paracellular transport

“…Other features that make the BBB a highly selective physical barrier include high mitochondrial content and polarized expression of transporters and metabolic enzymes [ 7 , 8 ]. Additionally, the brain microvascular endothelial cells respond to inflammatory stimuli through the expression of adhesion molecules and exhibit vascular endothelial characteristics [ 9 ]. These peculiar characteristics are required for the optimal functioning of the BBB to maintain a stable brain microenvironment.…”

Blood–Brain Barrier and Neurodegenerative Diseases—Modeling with iPSC-Derived Brain Cells

“…However, some of the generated ECs are found to lack EC-related gene expression, such as CD31. In addition, the transcription profile analysis reveals that these ECs lack some EC properties, so it may not be suitable for studying the cell interaction with pericytes and astrocytes [ 196 , 200 ]. Nishihara et al published a modified protocol claiming that their ECs can be used to investigate the interaction of the immune cells with ECs due to the constitutive cell surface expression of ICAM-1 and E-selectin, which are not found in ECs generated from previous protocols [ 198 ].…”

“…Although the cells express several brain EC properties and markers, the characterization has been mainly focused on the in vitro barrier properties. Recently, some questions have been raised against the cell identity of the brain ECs derived through these protocols (discussed in more detail in [ 196 ]). First, brain ECs have a specific inflammatory phenotype.…”

Drug Penetration into the Central Nervous System: Pharmacokinetic Concepts and In Vitro Model Systems

“…As described below, static models range from simple approaches based on genetically-modified epithelial cell lines for use in high-throughput screenings to more elaborate co-culture systems that incorporate multiple, CNS-derived primary or immortalized cell types to more closely recapitulate the unique barrier properties of the BBB in vivo. Another potential source of BMECs and other CNS cells for use in in vitro BBB models that has been reviewed in detail elsewhere are human pluripotent stem-cells [126][127][128][129][130].…”