BBB "in vitro"

The human brain is washed by cerebrospinal fluid (CSF), which supplies various nutrients and is necessary for the proper functioning of the brain. Modern understanding of the composition and production of human CSF is limited due to the lack of experimental access to it. Madeline Lancaster's group from the Laboratory of Molecular Biology in Cambridge, UK, has developed a new human brain organoid that produces CSF and can predict whether drugs are able to access the brain.

CSF is produced and secreted by the choroid plexus. It also filters the blood, acting as a barrier (blood-brain barrier, BBB) for most substances contained in the blood, and selectively providing access to some small molecules. To study the development and functioning of the human choroid plexus, including how CSF is produced, the group developed a new organoid model of this tissue.

Microscopic models of the choroid plexus from human stem cells have key features of the prototype. They are CSF-filled compartments that are isolated from the surrounding nutrient medium in which the organoids are grown.

Microscopic image of the convoluted epithelium of the choroid plexus in organoids expressing markers of dense contacts between endothelial cells and membrane transporters regulating the flow of molecules to the brain.

CSF produced by organoids contained known biomarkers of human CSF, the researchers were able to observe changes in the secretion of its components over time, as well as various cell types contributing to these dynamic changes in the composition of CSF. Researchers have discovered a previously unknown cell type in the choroid plexus – myoepithelial cells. These cells may be important for generating biomechanical forces necessary for CSF secretion.

A diagram of organoids of the choroid plexus producing CSF-like fluid surrounded from the outside by a dense barrier, which is similar to the BBB of the real human brain. The ability of drugs (for example, dopamine and levodopa) to overcome the BBB can be investigated by extracting fluid and analyzing for the presence of drugs in it.

The researchers also showed that the organoids of the choroid plexus form a dense barrier that exhibits the same selectivity for small molecules as in the human brain. Thus, organoids prevent the penetration of low-molecular dopamine, but skip its precursor, levodopa. Along with demonstrating the accuracy of the model, it also proves that choroid plexus organoids may have predictive potential for assessing BBB permeability for drugs under development. So, a drug that recently failed in phase 1 clinical trials, BIA-10-2474, was tested on organoids – the researchers were able to show that the drug would accumulate in the brain and exhibit neurotoxicity.

The structure of the blood-brain barrier differs in different animal species, so the presence of a human-specific model of the choroid plexus is important because of the ability to predict the permeability of the BBB for new drugs. This will lead to a reduction in the number of drugs that were approved for phase 1 clinical trials, but failed. This model is also important as a source of CSF, as close as possible to human CSF, as it will allow scientists to study the secretion of various factors and biomarkers whose functions are still insufficiently studied.

Article by L.Pellegrini et al. Human CNS barrier-forming organoids with cerebrospinal fluid production is published in the journal Science.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of MRC: Brain organoids with the potential to predict drug permeability.