The year in review: progress in brain barriers and brain fluid research in 2018

Keep, Richard F.; Jones, Hazel C.; Drewes, Lester R.

doi:10.1186/s12987-019-0124-y

Cited by 12 publications

(9 citation statements)

References 137 publications

(142 reference statements)

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“…Increasing data suggest that CSF circulation serves critical roles in brain maintenance ( Louveau et al, 2015 ; Da Mesquita et al, 2018a ; Mestre et al, 2020 ). Yet, specific mechanisms and pathways involved in CSF passage within intracranial cavities remain incompletely explained ( Keep et al, 2019 ; Rustenhoven et al, 2021 ). Historical literature asserts that AG protrude through dura, permitting CSF drainage into dural venous spaces (DVS, i.e., dural venous sinuses, dural veins, and lacunae; Kida et al, 1988 ; Kida et al, 1993 ; Welch and Pollay, 1961 ).…”

Section: Introductionmentioning

confidence: 99%

Arachnoid granulations are lymphatic conduits that communicate with bone marrow and dura-arachnoid stroma

Shah

Leurgans

Mehta

et al. 2022

Journal of Experimental Medicine

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Arachnoid granulations (AG) are poorly investigated. Historical reports suggest that they regulate brain volume by passively transporting cerebrospinal fluid (CSF) into dural venous sinuses. Here, we studied the microstructure of cerebral AG in humans with the aim of understanding their roles in physiology. We discovered marked variations in AG size, lobation, location, content, and degree of surface encapsulation. High-resolution microscopy shows that AG consist of outer capsule and inner stromal core regions. The fine and porous framework suggests uncharacterized functions of AG in mechanical CSF filtration. Moreover, internal cytokine and immune cell enrichment imply unexplored neuroimmune properties of these structures that localize to the brain–meningeal lymphatic interface. Dramatic age-associated changes in AG structure are additionally identified. This study depicts for the first time microscopic networks of internal channels that communicate with perisinus spaces, suggesting that AG subserve important functions as transarachnoidal flow passageways. These data raise new theories regarding glymphatic–lymphatic coupling and mechanisms of CSF antigen clearance, homeostasis, and diseases.

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Section: Introductionmentioning

confidence: 99%

Arachnoid granulations are lymphatic conduits that communicate with bone marrow and dura-arachnoid stroma

Shah

Leurgans

Mehta

et al. 2022

Journal of Experimental Medicine

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“…1 A ). These cells have been reported to meet the need for a reliable and reproducible in vitro model of the human BBB that can be used to screen drugs and understand mechanisms of neurological diseases ( 25 , 26 ). This benchmark protocol relies on performing a sequence of defined steps starting with the differentiation of PSCs into both neural and endothelial lineages.…”

mentioning

confidence: 99%

Pluripotent stem cell-derived epithelium misidentified as brain microvascular endothelium requires ETS factors to acquire vascular fate

Houghton

Magdeldin

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

139

152

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Cells derived from pluripotent sources in vitro must resemble those found in vivo as closely as possible at both transcriptional and functional levels in order to be a useful tool for studying diseases and developing therapeutics. Recently, differentiation of human pluripotent stem cells (hPSCs) into brain microvascular endothelial cells (ECs) with blood–brain barrier (BBB)-like properties has been reported. These cells have since been used as a robust in vitro BBB model for drug delivery and mechanistic understanding of neurological diseases. However, the precise cellular identity of these induced brain microvascular endothelial cells (iBMECs) has not been well described. Employing a comprehensive transcriptomic metaanalysis of previously published hPSC-derived cells validated by physiological assays, we demonstrate that iBMECs lack functional attributes of ECs since they are deficient in vascular lineage genes while expressing clusters of genes related to the neuroectodermal epithelial lineage (Epi-iBMEC). Overexpression of key endothelial ETS transcription factors (ETV2, ERG, and FLI1) reprograms Epi-iBMECs into authentic endothelial cells that are congruent with bona fide endothelium at both transcriptomic as well as some functional levels. This approach could eventually be used to develop a robust human BBB model in vitro that resembles the human brain EC in vivo for functional studies and drug discovery.

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“…Last, a limitation of the current study and many other in vitro models of NDs, such as 2D single-cell type cultures or brain organoidbased models, is the absence of a functional in vitro BBB. Although significant progress in modeling the neuro-vascular unit has been made and a number of in vitro models of the BBB have been devel-oped on the basis of iPSCs, cell lines, or human umbilical vein endothelial sources (54,68,69), in vivo-like function of the barrier is notoriously difficult to achieve. This stems from the fact that (i) the BBB is not composed of one single cell type but rather requires the interplay of a number of cells with varying ratios to achieve in vivo functionality, (ii) they are not static in their physiological behavior but highly dynamic in terms of permeability as well as the receptors and transporters they express as a response to changes in environment, and (iii) vascular barriers are not the same throughout the human body but rather specific.…”

Section: Discussionmentioning

confidence: 99%

Human physiomimetic model integrating microphysiological systems of the gut, liver, and brain for studies of neurodegenerative diseases

et al. 2021

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Slow progress in the fight against neurodegenerative diseases (NDs) motivates an urgent need for highly controlled in vitro systems to investigate organ-organ– and organ-immune–specific interactions relevant for disease pathophysiology. Of particular interest is the gut/microbiome-liver-brain axis for parsing out how genetic and environmental factors contribute to NDs. We have developed a mesofluidic platform technology to study gut-liver-cerebral interactions in the context of Parkinson’s disease (PD). It connects microphysiological systems (MPSs) of the primary human gut and liver with a human induced pluripotent stem cell–derived cerebral MPS in a systemically circulated common culture medium containing CD4+ regulatory T and T helper 17 cells. We demonstrate this approach using a patient-derived cerebral MPS carrying the PD-causing A53T mutation, gaining two important findings: (i) that systemic interaction enhances features of in vivo–like behavior of cerebral MPSs, and (ii) that microbiome-associated short-chain fatty acids increase expression of pathology-associated pathways in PD.

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The year in review: progress in brain barriers and brain fluid research in 2018

Cited by 12 publications

References 137 publications

Arachnoid granulations are lymphatic conduits that communicate with bone marrow and dura-arachnoid stroma

Arachnoid granulations are lymphatic conduits that communicate with bone marrow and dura-arachnoid stroma

Pluripotent stem cell-derived epithelium misidentified as brain microvascular endothelium requires ETS factors to acquire vascular fate

Human physiomimetic model integrating microphysiological systems of the gut, liver, and brain for studies of neurodegenerative diseases

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