Abstract
The integral selectivity characteristic of the blood brain barrier (BBB) limits therapeutic options for many neurologic diseases and disorders. Currently, very little is known about the mechanisms that govern the dynamic nature of the BBB. Recent reports have focused on the development and application of human brain organoids developed from neuro-progenitor cells. While these models provide an excellent platform to study the effects of disease and genetic aberrances on brain development, they may not model the microvasculature and BBB of the adult human cortex. To date, most in vitro BBB models utilize endothelial cells, pericytes and astrocytes. We report a 3D spheroid model of the BBB comprising all major cell types, including neurons, microglia and oligodendrocytes, to recapitulate more closely normal human brain tissue. Spheroids show expression of tight junctions, adherens junctions, adherens junction-associated proteins and cell specific markers. Functional assessment using MPTP, MPP+ and mercury chloride indicate charge selectivity through the barrier. Junctional protein distribution was altered under hypoxic conditions. Our spheroid model may have potential applications in drug discovery, disease modeling, neurotoxicity and cytotoxicity testing.
Highlights
IntroductionMicroglia play a critical role in blood brain barrier (BBB) regulation and modulation of tight junction expression
Morphology, and protein expression[16,17,18,19]
We report the development of a human neurovascular unit organoid model that contains the six constituent cell types found within the brain cortex: human brain microvascular endothelial cells (HBMEC), human pericytes (HBVP), human astrocytes (HA), human microglia (HM), human oligodendrocytes (HO) and human neurons (HN), with endothelial cells enclosing the brain parenchymal cells
Summary
Microglia play a critical role in BBB regulation and modulation of tight junction expression They in turn have complex integrations in brain diseases such as epilepsy, ischemic stroke, and neurodegenerative disorders[20]. A natural progression from the currently established BBB models would be to define the effect of chemical agents on all the cell types that are critical to the normal function of a human NVU, including the microglia, oligodendrocytes and neurons that are adjacent to the BBB, and to further understand the intercellular dynamics once molecules cross the barrier. The development of a 3D in vitro system that contains all major cell types found in adult human brain cortex may provide a platform that can be used to understand the fundamental principles at play with the BBB, its function, and to understand the effects of chemical substances that cross the BBB. A model of the blood brain barrier during clinical ischemia was established showing physiologic responses under hypoxic conditions
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