Why do we not have better drugs for treating neurodegenerative diseases?
Neurodegenerative diseases are a major global health concern that can be expensive to treat. The low success rate of promising drug candidates is one reason for the high cost, with only 8% of central nervous system drugs approved due to toxicity or ineffectiveness. This is partly due to the lack of human equivalent models in drug development which requires high-throughput drug testing. To address this challenge, researchers have developed 3D blood-brain barrier (BBB) models that are more representative of the BBB than current 2D models.
So how did Nzou et. al. create an organoid resembling the BBB?
The BBB is a complex system that is critical to maintaining the integrity of the human cerebrovascular unit. It depends on specific intercellular interactions within the human brain and is critical to maintaining the integrity of the human neurovascular unit. Cells such as astrocytes, oligodendrocytes, microglia, and neurons play critical roles in the regulation and modulation of the BBB, and their inclusion in an in vitro organoid model would help predict human physiologic conditions. Nzou et. al. developed a human neurovascular unit organoid model with six cell types found in the brain cortex: microvascular endothelial cells, pericytes, astrocytes, microglia, oligodendrocytes, and neurons. This model can be used to understand the fundamental principles of the BBB, its function, and the effects of chemical substances that cross the BBB. The model was validated for the expression of tight junctions, adherens junctions, and transport proteins and was shown to be useful in toxicity assessment studies for molecules that cross or open the BBB.
Nzou et. al. aimed to demonstrate the assembly and cellular organization of human brain organoids with four cell types using a hanging drop culture environment. Nzou et. al. found that HBMECs and HBVPs were localized to the periphery of the organoid, while HAs were near the surface and neuronal cells formed the core. They evaluated the presence of a blood-brain barrier (BBB) in the organoid model by testing the expression of the BBB tight junction protein ZO-1, claudin-5, adherens junction protein VE-cadherin, glucose transporter 1 (GLUT1), and permeability-glycoprotein (P-gp); which was found to be present. The model's BBB was found to be charge-selective, as evidenced by the effect of mercury ions and the small molecule pro-drug MPTP. The authors also confirmed the barrier by assessing FITC-labeled IgG permeability across the BBB. The results showed that IgG permeability was lower in untreated organoids than in organoids that were pretreated with histamine, a chemical agent that transiently opens the BBB. The authors then constructed organoids containing all six cell types and found that the organoids maintained high cell viability, and characterized the integrity and dynamic properties of the barrier formed in the organoids. The authors also found that hypoxia disrupts the localization of tight and adherens junction proteins, indicating that their organoid model may be useful in studying ischemia in a physiologically relevant environment.
So where can this organoid resembling the blood-brain barrier be useful?
In vitro BBB models are crucial for the screening and development of novel and effective therapies for neurological disorders. This model, which is based on cells derived from induced pluripotent stem cells from TempoBiosciences, can be used to understand the fundamental principles of the BBB, its function, and the effects of chemical substances that cross the BBB and its impact on microglia, oligodendrocytes, and neurons. This can be useful in studying neurodegenerative conditions such as Alzheimer's disease, multiple sclerosis, and ALS, as well as injury models like stroke. Organoids containing 4 or 3 cell types have functional barrier properties and can be useful in studying neurodegenerative conditions and injury models. Organoids with six cell types maintain high cell viability for up to 21 days, which is important for evaluating long-term drug toxicity.
Reference to the paper:
Nzou, G., Wicks, R.T., Wicks, E.E. et al. Human Cortex Spheroid with a Functional Blood-Brain Barrier for High-Throughput Neurotoxicity Screening and Disease Modeling. Sci Rep 8, 7413 (2018). https://doi.org/10.1038/s41598-018-25603-5
