A cellular and spatial map of the choroid plexus across brain ventricles and ages

Dani, Neil; Herbst, Rebecca H.; McCabe, Cristin; Green, Gilad S.; Kaiser, Karol; Head, Joshua P.; Cui, Jin; Shipley, Frederick B.; Jang, Ahram; Dionne, Danielle; Nguyễn, Lan; Rodman, Christopher; Riesenfeld, Samantha J.; Procházka, Jan; Procházková, Michaela; Sedláček, Radislav; Zhang, Feng; Bryja, Vı́tězslav; Rozenblatt-Rosen, Orit; Habib, Naomi; Regev, Aviv; Lehtinen, Maria K.

doi:10.1016/j.cell.2021.04.003

Cited by 201 publications

(172 citation statements)

References 103 publications

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“…The CP performs a multitude of important functions including CSF production, development, and maintenance of the periventricular neurogenic zones, neuroimmune communication, and delivery of micronutrients, growth factors, hormones and neurotrophins to the brain via the CSF, either from systemic blood through the leaky microvasculature or from the CP epithelium ( Ghersi-Egea et al, 2018 ; Kaiser and Bryja, 2020 ) or mesenchymal components ( Dani et al, 2021 ). The association between CP vascular, stromal, and epithelial components appears essential for CP functioning, also due to the presence of local signaling between epithelial cells, mesenchymal cells, and blood vessels.…”

Section: Discussionmentioning

confidence: 99%

“…In the rat, lateral CP vascular casts show parallel arteries feeding a flat, highly anastomosed capillary network draining into parallel veins that follow artery courses ( Sangiorgi et al, 2003 ), and in mouse immunolabeling shows tight straight arteries expressing claudin-5 and vWF+ veins following arteries and also coasting the CP free edge ( Dani et al, 2021 ). On the other hand, in the rat hCP venules were observed to be tortuous, but their connections to capillaries were not explored ( Sun and Hashimoto, 1991 ).…”

Section: Discussionmentioning

confidence: 99%

“…Despite its simple histology (a monostratified cuboid epithelium overlying a connective stroma vascularized by fenestrated capillaries) many aspects of CP functions are still unknown, especially because of its fragility, convoluted shape, and deep location within the brain. So far, the studies observing CP cellular responses in situ have shown its interactions with factors in blood and CSF ( Cui et al, 2020 ; Shipley et al, 2020 ); however, within a single CP, epithelial cells are heterogeneous in their developmental origin (reviewed in Lun M. et al, 2015 ) and protein expression ( Lun M. P. et al, 2015 ; Dani et al, 2021 ), especially in relation to intercellular contact ( Lobas et al, 2012 ), and it is not clear whether this heterogeneity translates into spatial differences in CP function. It is known that within ventricles there are CSF currents ( Faubel et al, 2016 ) which would differentially expose the various parts of the ventricular surface to substances released into the CSF ( Kreeger et al, 2018 ), and points of contact of the CP fronds to the ventricular surface have sporadically been described ( Terr and Edgerton, 1985 ).…”

Section: Introductionmentioning

confidence: 99%

“…Scanning electron microscopy of CP vascular casts from various animals and ventricles have given an overview of vascular network arrangement ( Meunier et al, 2013 ). A recent single-cell and single-nucleus RNA sequencing study has provided a cellular atlas of developing, adult and aging mouse CP across all brain ventricles, and displayed the spatial distribution of specific RNAs and proteins ( Dani et al, 2021 ). However, these studies do not yield enough spatial details to fully reconstruct the connection topology of CP vascular networks and, due to CP isolation from the brain, are unable to assess correlations between vascular patterns, epithelial folding, and ventricular localization.…”

Section: Introductionmentioning

confidence: 99%

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3D Reconstruction of the Clarified Rat Hindbrain Choroid Plexus

Perin

Ricci

et al. 2021

Front. Cell Dev. Biol.

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The choroid plexus (CP) acts as a regulated gate between blood and cerebrospinal fluid (CSF). Despite its simple histology (a monostratified cuboidal epithelium overlying a vascularized stroma), this organ has remarkably complex functions several of which involve local interaction with cells located around ventricle walls. Our knowledge of CP structural organization is mainly derived from resin casts, which capture the overall features but only allow reconstruction of the vascular pattern surface, unrelated to the overlying epithelium and only loosely related to ventricular location. Recently, CP single cell atlases are starting to emerge, providing insight on local heterogeneities and interactions. So far, however, few studies have described CP spatial organization at the mesoscale level, because of its fragile nature and deep location within the brain. Here, using an iDISCO-based clearing approach and light-sheet microscopy, we have reconstructed the normal rat hindbrain CP (hCP) macro- and microstructure, using markers for epithelium, arteries, microvasculature, and macrophages, and noted its association with 4th ventricle-related neurovascular structures. The hCP is organized in domains associated to a main vessel (fronds) which carry a variable number of villi; the latter are enclosed by epithelium and may be flat (leaf-like) or rolled up to variable extent. Arteries feeding the hCP emerge from the cerebellar surface, and branch into straight arterioles terminating as small capillary anastomotic networks, which run within a single villus and terminate attaching multiple times to a large tortuous capillary (LTC) which ends into a vein. Venous outflow mostly follows arterial pathways, except for the lateral horizontal segment (LHS) and the caudal sagittal segment. The structure of fronds and villi is related to the microvascular pattern at the hCP surface: when LTCs predominate, leaflike villi are more evident and bulge from the surface; different, corkscrew-like villi are observed in association to arterioles reaching close to the CP surface with spiraling capillaries surrounding them. Both leaf-like and corkscrew-like villi may reach the 4th ventricle floor, making contact points at their tip, where no gap is seen between CP epithelium and ependyma. Contacts usually involve several adjacent villi and may harbor epiplexus macrophages. At the junction between medial (MHS) and lateral (LHS) horizontal segment, arterial supply is connected to the temporal bone subarcuate fossa, and venous outflow drains to a ventral vein which exits through the cochlear nuclei at the Luschka foramen. These vascular connections stabilize the hCP overall structure within the 4th ventricle but make MHS-LHS joint particularly fragile and very easily damaged when removing the brain from the skull. Even in damaged samples, however, CP fronds (or isolated villi) often remain strongly attached to the dorsal cochlear nucleus (DCN) surface; in these fronds, contacts are still present and connecting “bridges” may be seen, suggesting the presence of real molecular contacts rather than mere appositions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

3D Reconstruction of the Clarified Rat Hindbrain Choroid Plexus

Perin

Ricci

et al. 2021

Front. Cell Dev. Biol.

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“…ECs in the ChP are fenestrated to allow the passage of water and small molecules. The blood-CSF barrier at the ChP is instead formed by a layer of epithelial cells surrounding choroidal vessels that regulate the permeability by expressing junctional proteins and membrane transporters (Dani et al, 2021 ).…”

Section: Endothelial Cellsmentioning

confidence: 99%

Location Matters: Navigating Regional Heterogeneity of the Neurovascular Unit

Bernier

Brunner

Cottarelli

et al. 2021

Front. Cell. Neurosci.

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The neurovascular unit (NVU) of the brain is composed of multiple cell types that act synergistically to modify blood flow to locally match the energy demand of neural activity, as well as to maintain the integrity of the blood-brain barrier (BBB). It is becoming increasingly recognized that the functional specialization, as well as the cellular composition of the NVU varies spatially. This heterogeneity is encountered as variations in vascular and perivascular cells along the arteriole-capillary-venule axis, as well as through differences in NVU composition throughout anatomical regions of the brain. Given the wide variations in metabolic demands between brain regions, especially those of gray vs. white matter, the spatial heterogeneity of the NVU is critical to brain function. Here we review recent evidence demonstrating regional specialization of the NVU between brain regions, by focusing on the heterogeneity of its individual cellular components and briefly discussing novel approaches to investigate NVU diversity.

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