Brain barrier and support in a dish
Deep within the brain, the choroid plexus filters blood and secretes cerebrospinal fluid (CSF), a nutrient-rich liquid that bathes and supports the brain and protects it from entry of toxic compounds. Current understanding of this vital tissue in humans is limited. Pellegrini et al. developed choroid plexus organoids that quantitatively predict human brain permeability of small molecules and secrete an isolated CSF-like fluid (see the Perspective by Silva-Vargas and Doetsch). This CSF model reveals secretion of developmental factors and disease-related biomarkers by key cell types and provides a testing ground for drug entry into the brain.
Science, this issue p. eaaz5626; see also p. 143
The choroid plexus is a secretory epithelial tissue of the central nervous system (CNS) responsible for cerebrospinal fluid (CSF) production and functions as a barrier that regulates entry of compounds and nutrients into the brain. The CSF plays key roles in the delivery of nutrients to the brain, circulation of instructive signaling molecules, and clearance of toxic by-products such as protein aggregates.
Current understanding of the choroid plexus and CSF has primarily come from animal models or CSF collected from human volunteers. These have yielded insight into general CSF composition, but the specific cellular and tissue sources of various secreted proteins have remained elusive. There is also limited understanding of the development of the choroid plexus in humans and of the relative changes in CSF composition over time. All of these deficiencies in our understanding come from a lack of experimental access to the human choroid plexus. Although several previous studies have successfully generated cells with a choroid plexus identity from human pluripotent stem cells, none have been able to recapitulate the morphology, maturation, and function of the choroid plexus, and currently, no in vitro model exists for authentic human CSF. Knowledge of the processes that regulate choroid plexus development and CSF composition could provide better strategies to manipulate and therapeutically target this vital brain tissue.
To study the development and function of the human choroid plexus, we developed a pluripotent stem cellderived organoid model. Choroid plexus organoids recapitulate key morphological and functional features of human choroid plexus. First, organoids form a tight barrier that selectively regulates the entry of small molecules such as dopamine. We demonstrate that organoids can qualitatively and quantitatively predict the permeability of new drugs, and we take advantage of this system to reveal a potential toxic accumulation of BIA 10-2474, a drug that caused severe neurotoxicity only in humans and not in animal models tested. Second, choroid plexus organoids secrete a CSF-like fluid containing proteins and known biomarkers within self-contained compartments. We examine changes in secretion of CSF proteins over time and identify distinct cell types within the epithelium that contribute to dynamic changes in CSF composition. We find that these cell types can be traced to rather obscure descriptions in the literature of dark and light cells, and we demonstrate that these cells exhibit opposing features related to mitochondria and cilia. We also uncover a previously unidentified cell type in the choroid plexus: myoepithelial cells. These interacting subpopulations exhibit distinct secretory roles in CSF production and reveal previously uncharacterized human-specific secreted proteins that may play important roles in human brain development.
Human choroid plexus organoids provide an easily tractable system to study the key functions of this organ: CSF secretion and selective transport into the CNS. As such, they can predict CNS permeability of new compounds to aid in the development of neurologically relevant therapeutics. They also provide a source of more authentic CSF and can be used to understand development of this key organ in brain development and homeostasis.
Choroid plexus organoids develop highly intricate folded tissue morphology (section stained for choroid plexus markers shown at top right) similar to choroid plexus tissue in vivo (top left) and, later, self-contained fluid-filled compartments containing a CSF-like fluid (top middle) that is separate from media. (Bottom left) Choroid plexus organoids accurately predict the permeability of small molecules such as dopamine and levodopa (l-dopa) and quantitatively predict the permeability of a range of therapeutic molecules. The graph shows the correlation between permeability in vivo and in vitro for the drugs tested. R2, coefficient of determination. (Bottom right) Single-cell RNA sequencing reveals newly identified epithelial subtypes (colored dark and light) that participate in filtration and specialized secretion of CSF proteins. The Venn diagram shows overlap between proteins detected in CSF in vivo and in the organoid.
Cerebrospinal fluid (CSF) is a vital liquid, providing nutrients and signaling molecules and clearing out toxic by-products from the brain. The CSF is produced by the choroid plexus (ChP), a protective epithelial barrier that also prevents free entry of toxic molecules or drugs from the blood. Here, we establish human ChP organoids with a selective barrier and CSF-like fluid secretion in self-contained compartments. We show that this in vitro barrier exhibits the same selectivity to small molecules as the ChP in vivo and that ChP-CSF organoids can predict central nervous system (CNS) permeability of new compounds. The transcriptomic and proteomic signatures of ChP-CSF organoids reveal a high degree of similarity to the ChP in vivo. Finally, the intersection of single-cell transcriptomics and proteomic analysis uncovers key human CSF components produced by previously unidentified specialized epithelial subtypes.
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Human CNS barrier-forming organoids with cerebrospinal fluid production - Science Magazine
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