2 Human CNS Barrier-Forming Organoids With Cerebrospinal Fluid Production

20/9/21 12:10 Human CNS barrier-forming organoids with cerebrospinal fluid production
HOME  SCIENCE  VOL. 369, NO. 6500  HUMAN CNS BARRIER-FORMING ORGANOIDS WITH CEREBROSPINAL FLUID PRODUCTION
RESEARCH ARTICLE
 󡀆 
Human CNS barrier-forming organoids with cerebrospinal fluid

production
LAURA PELLEGRINI
, CLAUDIA BONFIO , JESSICA CHADWICK, FARIDA BEGUM, MARK SKEHEL , AND , MADELINE A. LANCASTER  Authors Info & Affiliations
SCIENCE • 10 Jul 2020 • Vol 369, Issue 6500 • DOI: 10.1126/science.aaz5626
5 60     GET ACCESS
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 understand-
ing of this vital tissue in humans is limited. Pellegrini et al. developed choroid plexus organoids that quantita-
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tively predict human brain permeability of small molecules and secrete an isolated CSF-like fluid (see the
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Perspective by Silva-Vargas and Doetsch). This CSF model reveals secretion of developmental factors and dis-
ease-related biomarkers by key cell types and provides a testing ground for drug entry into the brain.
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Science, this issue p. eaaz5626; see also p. 143 

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Structured Abstract 
INTRODUCTION
The choroid plexus is a secretory epithelial tissue of the central nervous system (CNS) responsible for cere-
brospinal 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 sig-
naling molecules, and clearance of toxic by-products such as protein aggregates.
RATIONALE
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.
RESULTS
To study the development and function of the human choroid plexus, we developed a pluripotent stem cell–
derived 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 mole-
cules such as dopamine. We demonstrate that organoids can qualitatively and quantitatively predict the per-
meability 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,
https://www.science.org/doi/10.1126/science.aaz5626 1/14
choroid plexus organoids secrete a CSF-like fluid containing proteins and known biomarkers within self-con-
tained 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 demon-
strate 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 dis-
tinct secretory roles in CSF production and reveal previously uncharacterized human-specific secreted proteins
that may play important roles in human brain development.
CONCLUSION
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 com-
pounds 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.
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CSF-producing choroid plexus organoids predict CNS permeability of drugs.

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.
Abstract
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 pro-
duced by previously unidentified specialized epithelial subtypes.
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Supplementary Material 
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Summary
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Materials and Methods
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Figs. S1 to S13
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Tables S1 to S5
References (50–128)
MDAR Reproducibility Checklist
Data S1 to S3
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Correction (9 July 2020): A new reference 98 was added to the supplementary reference list.
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