The Challenges of Choosing Blood-Brain Barrier Neurodevelopmental Models

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Disruptions in blood-brain barrier (BBB) integrity and permeability early in life are associated with neurodevelopmental disorders. These alterations also increase the possibility and ease for chemicals to travel into the brain, which may not otherwise occur. Unfortunately, most BBB models utilized are in adult animals and cannot answer outstanding questions regarding development exposures. The “Scaling Barriers: Cellular Dynamics and Models of Blood-Brain Barrier Developmental Toxicity” Symposium during the SOT 58th Annual Meeting and ToxExpo addressed this issue by introducing developmental models of the BBB in mice, zebrafish, and human cells and in a computational neurovascular unit system.

The presentation that really focused on a model for broad utility was that of Dr. Birgit Obermeier from Biogen. She described human cell culture models of the BBB to study function, integrity, permeability, and improved drug delivery. Common challenges researchers face when using BBB models can include difficulties recapitulating the BBB characteristics observed in vivo, such as the tight and highly restrictive nature of BBB endothelial cells, presence of influx and efflux transporters, and occurrence of endosomal sorting mechanisms.

Dr. Obermeier discussed multiple in vitro models that overcome these challenges and are both high-throughput and translatable. There are many human cell culture BBB models available, but very few offer high-throughput capabilities while being highly physiologically relevant. For example, a high-throughput model with low physiological relevance is the simple 2D transwell membrane traditional culture, which is among the most commonly used. To move toward more physiologically relevant approaches, organoids are increasing in popularity, especially with the commercially available Mimetas OrganoPlates. This approach offers the best of both worlds with a high-throughput format including automation potential (around 40 BBB samples per plate), greater relevance to human BBB physiology with a coculture of pericytes and astrocytes, and incorporation of flow, though not controlled. Overall, there are definitely limitations to any of the in vitro BBB models discussed, but searching for those with high physiological relevance that most closely recapitulate the 3D anatomy of the BBB in vivo seems to have the greatest potential for answering questions on integrity, permeability, and drug delivery.

As a researcher interested in developmental neurotoxicity, I was naturally attracted to this Symposium. The session had many informative talks about various alternative models of the BBB during development. Each of the models discussed had its own advantages, suggesting that these models will be best used as “fit for purpose.”

This blog was prepared by an SOT Reporter. SOT Reporters are SOT members who volunteer to write about sessions and events they attend during the SOT Annual Meeting and ToxExpo. If you are interested in participating in the SOT Reporter program in the future, please email Giuliana Macaluso.

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