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Cell May 2021The choroid plexus (ChP) in each brain ventricle produces cerebrospinal fluid (CSF) and forms the blood-CSF barrier. Here, we construct a single-cell and spatial atlas...
The choroid plexus (ChP) in each brain ventricle produces cerebrospinal fluid (CSF) and forms the blood-CSF barrier. Here, we construct a single-cell and spatial atlas of each ChP in the developing, adult, and aged mouse brain. We delineate diverse cell types, subtypes, cell states, and expression programs in epithelial and mesenchymal cells across ages and ventricles. In the developing ChP, we predict a common progenitor pool for epithelial and neuronal cells, validated by lineage tracing. Epithelial and fibroblast cells show regionalized expression by ventricle, starting at embryonic stages and persisting with age, with a dramatic transcriptional shift with maturation, and a smaller shift in each aged cell type. With aging, epithelial cells upregulate host-defense programs, and resident macrophages upregulate interleukin-1β (IL-1β) signaling genes. Our atlas reveals cellular diversity, architecture and signaling across ventricles during development, maturation, and aging of the ChP-brain barrier.
Topics: Age Factors; Aging; Animals; Blood-Brain Barrier; Brain; Brain Diseases; Cell Differentiation; Cell Lineage; Choroid Plexus; Epithelial Cells; Female; Male; Mice; Mice, Inbred C57BL; Signal Transduction; Single-Cell Analysis
PubMed: 33932339
DOI: 10.1016/j.cell.2021.04.003 -
Nature Reviews. Neuroscience Aug 2015The choroid plexus (ChP) is the principal source of cerebrospinal fluid (CSF), which has accepted roles as a fluid cushion and a sink for nervous system waste in... (Review)
Review
The choroid plexus (ChP) is the principal source of cerebrospinal fluid (CSF), which has accepted roles as a fluid cushion and a sink for nervous system waste in vertebrates. Various animal models have provided insights into how the ChP-CSF system develops and matures. In addition, recent studies have uncovered new, active roles for this dynamic system in the regulation of neural stem cells, critical periods and the overall health of the nervous system. Together, these findings have brought about a paradigm shift in our understanding of brain development and health, and have stimulated new initiatives for the treatment of neurological disease.
Topics: Animals; Cerebrospinal Fluid; Choroid Plexus; Humans
PubMed: 26174708
DOI: 10.1038/nrn3921 -
The Journal of Neuroscience : the... Sep 2021Throughout the body, lymphatic fluid movement supports critical functions including clearance of excess fluid and metabolic waste. The glymphatic system is the analog of... (Review)
Review
Throughout the body, lymphatic fluid movement supports critical functions including clearance of excess fluid and metabolic waste. The glymphatic system is the analog of the lymphatic system in the CNS. As such, the glymphatic system plays a key role in regulating directional interstitial fluid movement, waste clearance, and, potentially, brain immunity. The glymphatic system enables bulk movement of CSF from the subarachnoid space along periarterial spaces, where it mixes with interstitial fluid within the parenchyma before ultimately exiting from the parenchyma via perivenous spaces. This review focuses on important questions about the structure of this system, why the brain needs a fluid transport system, and unexplored aspects of brain fluid transport. We provide evidence that astrocytes and blood vessels determine the shape of the perivascular space, ultimately controlling the movement of perivascular fluid. Glymphatic fluid movement has the potential to alter local as well as global transport of signaling molecules and metabolites. We also highlight the evidence for cross talk among the glymphatic system, cardiovascular system, gastrointestinal tract, and lymphatic system. Much remains to be studied, but we propose that the glymphatic/lymphatic system acts as a cornerstone in signaling between the brain and body.
Topics: Animals; Astrocytes; Brain; Choroid Plexus; Glymphatic System; Humans; Neurobiology
PubMed: 34526407
DOI: 10.1523/JNEUROSCI.0619-21.2021 -
Science (New York, N.Y.) Jul 2020Cerebrospinal 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...
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.
Topics: Blood-Brain Barrier; Cell Culture Techniques; Cerebrospinal Fluid; Cerebrospinal Fluid Proteins; Choroid Plexus; Gene Expression Profiling; Humans; Organoids; Proteomics; Single-Cell Analysis
PubMed: 32527923
DOI: 10.1126/science.aaz5626 -
Physiological Reviews Oct 2013The choroid plexus epithelium is a cuboidal cell monolayer, which produces the majority of the cerebrospinal fluid. The concerted action of a variety of integral... (Review)
Review
The choroid plexus epithelium is a cuboidal cell monolayer, which produces the majority of the cerebrospinal fluid. The concerted action of a variety of integral membrane proteins mediates the transepithelial movement of solutes and water across the epithelium. Secretion by the choroid plexus is characterized by an extremely high rate and by the unusual cellular polarization of well-known epithelial transport proteins. This review focuses on the specific ion and water transport by the choroid plexus cells, and then attempts to integrate the action of specific transport proteins to formulate a model of cerebrospinal fluid secretion. Significant emphasis is placed on the concept of isotonic fluid transport across epithelia, as there is still surprisingly little consensus on the basic biophysics of this phenomenon. The role of the choroid plexus in the regulation of fluid and electrolyte balance in the central nervous system is discussed, and choroid plexus dysfunctions are described in a very diverse set of clinical conditions such as aging, Alzheimer's disease, brain edema, neoplasms, and hydrocephalus. Although the choroid plexus may only have an indirect influence on the pathogenesis of these conditions, the ability to modify epithelial function may be an important component of future therapies.
Topics: Animals; Carrier Proteins; Cerebrospinal Fluid; Choroid Plexus; Humans; Models, Animal; Water-Electrolyte Balance
PubMed: 24137023
DOI: 10.1152/physrev.00004.2013 -
Nature Jul 2021Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms. However, an unbiased...
Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms. However, an unbiased understanding of the cellular and molecular processes that are affected in the brains of patients with COVID-19 is missing. Here we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control individuals (including 1 patient with terminal influenza) and 8 patients with COVID-19. Although our systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations indicating that barrier cells of the choroid plexus sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover microglia and astrocyte subpopulations associated with COVID-19 that share features with pathological cell states that have previously been reported in human neurodegenerative disease. Synaptic signalling of upper-layer excitatory neurons-which are evolutionarily expanded in humans and linked to cognitive function-is preferentially affected in COVID-19. Across cell types, perturbations associated with COVID-19 overlap with those found in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia and depression. Our findings and public dataset provide a molecular framework to understand current observations of COVID-19-related neurological disease, and any such disease that may emerge at a later date.
Topics: Aged; Aged, 80 and over; Astrocytes; Brain; COVID-19; Cell Nucleus; Choroid Plexus; Female; Humans; Inflammation; Male; Microglia; Middle Aged; Neurons; SARS-CoV-2; Single-Cell Analysis; Transcriptome; Virus Replication
PubMed: 34153974
DOI: 10.1038/s41586-021-03710-0 -
Cell Stem Cell Dec 2020Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, leads to respiratory symptoms that can be fatal....
Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, leads to respiratory symptoms that can be fatal. However, neurological symptoms have also been observed in some patients. The cause of these complications is currently unknown. Here, we use human-pluripotent-stem-cell-derived brain organoids to examine SARS-CoV-2 neurotropism. We find expression of viral receptor ACE2 in mature choroid plexus cells expressing abundant lipoproteins, but not in neurons or other cell types. We challenge organoids with SARS-CoV-2 spike pseudovirus and live virus to demonstrate viral tropism for choroid plexus epithelial cells but little to no infection of neurons or glia. We find that infected cells are apolipoprotein- and ACE2-expressing cells of the choroid plexus epithelial barrier. Finally, we show that infection with SARS-CoV-2 damages the choroid plexus epithelium, leading to leakage across this important barrier that normally prevents entry of pathogens, immune cells, and cytokines into cerebrospinal fluid and the brain.
Topics: Angiotensin-Converting Enzyme 2; Animals; Blood-Brain Barrier; Chlorocebus aethiops; Choroid Plexus; HEK293 Cells; Humans; Models, Biological; Organoids; SARS-CoV-2; Vero Cells; Viral Tropism; Virus Internalization
PubMed: 33113348
DOI: 10.1016/j.stem.2020.10.001 -
Pediatric Neurosurgery 2022Choroid plexectomy was first performed around 1910. Later, the technique evolved into subtotal choroid plexus cauterization (CPC) but was largely abandoned following the... (Review)
Review
BACKGROUND
Choroid plexectomy was first performed around 1910. Later, the technique evolved into subtotal choroid plexus cauterization (CPC) but was largely abandoned following the invention of the ventriculoperitoneal shunt. Over time, with improved understanding of the pathophysiology of hydrocephalus and improvement in endoscopic techniques and equipment, the procedure of CPC was reintroduced. However, little is known about the biomolecular consequences of ablation of a significant portion of the choroid plexus on metabolic brain homeostasis, neurogenesis, and neuroimmunology.
SUMMARY
The physiological functions of choroid plexus in neurogenesis and neuroimmunology and its role in diseases, such as AD and MS, should alert to possible as yet to be determined consequences. Studies, both in children and in adults, are needed not only on the success in hydrodynamic stabilization of hydrocephalus but also on the long-term outcome, especially premature neurodegeneration and inflammatory changes and on compensatory metabolic mechanisms.
KEY MESSAGES
The value of CPC for treatment of hydrocephalus in medically underserved areas should be remembered, yet when alternative treatment options are available, we cannot responsibly advocate against or for the use of CPC. Therefore, perhaps a more detailed discussion of risks and benefits of a CPC with parents would be best to include the possible implications in brain development and function.
Topics: Child; Adult; Humans; Infant; Choroid Plexus; Ventriculoperitoneal Shunt; Hydrocephalus; Cautery; Endoscopy
PubMed: 35960323
DOI: 10.1159/000526488 -
Fluids and Barriers of the CNS Sep 2022The choroid plexus is situated at an anatomically and functionally important interface within the ventricles of the brain, forming the blood-cerebrospinal fluid barrier... (Review)
Review
The choroid plexus is situated at an anatomically and functionally important interface within the ventricles of the brain, forming the blood-cerebrospinal fluid barrier that separates the periphery from the central nervous system. In contrast to the blood-brain barrier, the choroid plexus and its epithelial barrier have received considerably less attention. As the main producer of cerebrospinal fluid, the secretory functions of the epithelial cells aid in the maintenance of CNS homeostasis and are capable of relaying inflammatory signals to the brain. The choroid plexus acts as an immunological niche where several types of peripheral immune cells can be found within the stroma including dendritic cells, macrophages, and T cells. Including the epithelia cells, these cells perform immunosurveillance, detecting pathogens and changes in the cytokine milieu. As such, their activation leads to the release of homing molecules to induce chemotaxis of circulating immune cells, driving an immune response at the choroid plexus. Research into the barrier properties have shown how inflammation can alter the structural junctions and promote increased bidirectional transmigration of cells and pathogens. The goal of this review is to highlight our foundational knowledge of the choroid plexus and discuss how recent research has shifted our understanding towards viewing the choroid plexus as a highly dynamic and important contributor to the pathogenesis of neurological infections. With the emergence of several high-profile diseases, including ZIKA and SARS-CoV-2, this review provides a pertinent update on the cellular response of the choroid plexus to these diseases. Historically, pharmacological interventions of CNS disorders have proven difficult to develop, however, a greater focus on the role of the choroid plexus in driving these disorders would provide for novel targets and routes for therapeutics.
Topics: Blood-Brain Barrier; Brain; COVID-19; Choroid Plexus; Humans; SARS-CoV-2; Zika Virus; Zika Virus Infection
PubMed: 36088417
DOI: 10.1186/s12987-022-00372-6 -
Brain : a Journal of Neurology Oct 2023Myotonic dystrophy type 1 is a dominantly inherited multisystemic disease caused by CTG tandem repeat expansions in the DMPK 3' untranslated region. These expanded...
Myotonic dystrophy type 1 is a dominantly inherited multisystemic disease caused by CTG tandem repeat expansions in the DMPK 3' untranslated region. These expanded repeats are transcribed and produce toxic CUG RNAs that sequester and inhibit activities of the MBNL family of developmental RNA processing factors. Although myotonic dystrophy is classified as a muscular dystrophy, the brain is also severely affected by an unusual cohort of symptoms, including hypersomnia, executive dysfunction, as well as early onsets of tau/MAPT pathology and cerebral atrophy. To address the molecular and cellular events that lead to these pathological outcomes, we recently generated a mouse Dmpk CTG expansion knock-in model and identified choroid plexus epithelial cells as particularly affected by the expression of toxic CUG expansion RNAs. To determine if toxic CUG RNAs perturb choroid plexus functions, alternative splicing analysis was performed on lateral and hindbrain choroid plexi from Dmpk CTG knock-in mice. Choroid plexus transcriptome-wide changes were evaluated in Mbnl2 knockout mice, a developmental-onset model of myotonic dystrophy brain dysfunction. To determine if transcriptome changes also occurred in the human disease, we obtained post-mortem choroid plexus for RNA-seq from neurologically unaffected (two females, three males; ages 50-70 years) and myotonic dystrophy type 1 (one female, three males; ages 50-70 years) donors. To test that choroid plexus transcriptome alterations resulted in altered CSF composition, we obtained CSF via lumbar puncture from patients with myotonic dystrophy type 1 (five females, five males; ages 35-55 years) and non-myotonic dystrophy patients (three females, four males; ages 26-51 years), and western blot and osmolarity analyses were used to test CSF alterations predicted by choroid plexus transcriptome analysis. We determined that CUG RNA induced toxicity was more robust in the lateral choroid plexus of Dmpk CTG knock-in mice due to comparatively higher Dmpk and lower Mbnl RNA levels. Impaired transitions to adult splicing patterns during choroid plexus development were identified in Mbnl2 knockout mice, including mis-splicing previously found in Dmpk CTG knock-in mice. Whole transcriptome analysis of myotonic dystrophy type 1 choroid plexus revealed disease-associated RNA expression and mis-splicing events. Based on these RNA changes, predicted alterations in ion homeostasis, secretory output and CSF composition were confirmed by analysis of myotonic dystrophy type 1 CSF. Our results implicate choroid plexus spliceopathy and concomitant alterations in CSF homeostasis as an unappreciated contributor to myotonic dystrophy type 1 CNS pathogenesis.
Topics: Humans; Female; Mice; Animals; Myotonic Dystrophy; Choroid Plexus; RNA-Binding Proteins; Alternative Splicing; RNA; Mice, Knockout; Trinucleotide Repeat Expansion
PubMed: 37143315
DOI: 10.1093/brain/awad148