Exploring the source of human brain fluids

doi:10.1126/science.abd0269

GSTDTAP > 气候变化

DOI	10.1126/science.abd0269
	Exploring the source of human brain fluids
	Violeta Silva-Vargas; Fiona Doetsch
	2020-07-10
发表期刊	Science
出版年	2020
英文摘要	The cerebrospinal fluid (CSF) is an optically clear but molecularly complex liquid that flows within the brain ventricles. It cushions the brain and delivers nutrients and signaling molecules while removing others. The CSF is produced by the choroid plexus (ChP), an understudied epithelial barrier that regulates the entry of factors from the blood into CSF and is also highly secretory. As a central hub with multiple functions, the ChP is emerging as a key contributor to normal brain physiology and disease ([ 1 ][1]). A lack of tools has limited exploration of the ChP, especially in humans. On page 159 of this issue, Pellegrini et al. ([ 2 ][2]) establish human ChP organoids, three-dimensional multicellular in vitro structures. They form compartments filled with a CSF-like fluid and exhibit functional barrier and secretion properties, resembling those in vivo. They are a powerful tool to predict drug permeability and investigate ChP secretion and cell diversity. The CSF is a complex and dynamic milieu whose composition changes at different stages of development, in adulthood and with aging, as well as in different physiological states ([ 1 ][1], [ 3 ][3], [ 4 ][4]). CSF composition even varies diurnally in adults. A variety of biologically active moieties—including signaling and growth factors, hormones, lipoproteins, neurotransmitters, extracellular matrix, and extracellular vesicles—are present in the CSF ([ 1 ][1], [ 3 ][3]). The ChP is a key, though not exclusive, source and transport route of factors in the CSF. The ChP and CSF together form a highly tuned flowing milieu integrating the delivery of local and long-range factors that affect processes, including stem cell proliferation, during development and adulthood, as well as neural circuit plasticity and brain physiology ([ 1 ][1], [ 3 ][3], [ 5 ][5]–[ 8 ][6]). The ChP is a highly vascularized structure anchored to the wall of the brain ventricle and floating in the CSF, with multiple key functions ([ 1 ][1], [ 4 ][4], [ 9 ][7]). It consists of a single outer epithelial cell layer surrounding an inner layer with fenestrated blood vessels, multiple stromal cell types, and surveilling immune cells ([ 1 ][1]). Cuboidal choroidal epithelial cells are highly polarized. Their apical side contains many villi and/or cilia and contacts the CSF. They are interconnected by tight junctions, forming the blood-CSF barrier, and tightly regulate access of factors from the blood into the CSF (see the figure). Choroidal epithelial cells are metabolically active and a key site for synthesis and modification of numerous polypeptides and detoxification of metabolites from the CSF. They are highly secretory, with large numbers of multivesicular bodies. Although epithelial cells are the major source of secreted factors in vivo, all ChP cell types can contribute to the CSF. ![Figure][8] The multifunctional choroid plexus A choroid plexus (ChP) is found in each brain ventricle and makes the cerebrospinal fluid (CSF). Chorodial epithelial cells are interconnected by tight junctions to form the blood-CSF barrier. Other ChP functions include secretion, detoxification, and immune surveillance. GRAPHIC: V. ALTOUNIAN/ SCIENCE Two-dimensional cultures of primary and embryonic stem cell–derived choroidal epithelial cells have provided important insight into ChP function. Organoids are self-organizing, three-dimensional structures, which more completely capture tissue complexity ([ 10 ][9]). ChP tissue has previously been induced in brain organoids ([ 11 ][10]). Pellegrini et al. have developed a protocol for the robust generation of human ChP organoids from pluripotent embryonic stem cells that contain polarized epithelial cells, with tight junctions that develop barrier properties and secrete a clear liquid that resembles in vivo CSF into a self-contained compartment. A key issue for all organoid systems is which developmental stage they model and how mature the cells become. Single-cell RNA sequencing and characterization of the ChP organoids revealed progressively mature epithelial cells and increasing numbers of stromal cells in older organoids that resemble the cellular organization and molecular profiles of in vivo human ChP tissue. Likewise, proteomics of the CSF-like fluid over time showed that the organoid CSF composition underwent a progressive maturation to postnatal stages. A major challenge in medicine is to deliver drugs to the brain, owing to the blood-CSF and blood-brain barriers. The blood-CSF barrier in the ChP is a highly regulated system, allowing the selective transport or passage of key macromolecules and small molecules ([ 9 ][7]). The human ChP organoids reported by Pellegrini et al. display barrier properties that predict drug permeability. Sampling the CSF-like fluid after exposing the organoids to different drugs in the medium revealed that the system recapitulates the (in)ability of known compounds, including antidepressants and chemotheraputic agents, to cross the barrier and showed the accumulation in organoid fluid of a preclinical drug that induced neurotoxicity in patients. Thus, ChP-CSF organoids may be a powerful screening platform for assessing and predicting blood-CSF drug permeability in humans. Morphologically, light and dark epithelial cells have been described in vivo by electron microscopy ([ 12 ][11]). Single-cell RNA sequencing of human ChP organoids identified multiple epithelial cell subtypes with distinct molecular signatures: light and dark cells, which Pellegrini et al. show are enriched in ciliary versus mitochondrial genes, respectively, and an undescribed population of myoepithelial cells, which are contractile cells found in other secretory organs. These subtypes of epithelial cells showed differences in their secretory profiles. Future characterization of the stromal cells found in the organoids and the addition of other cell types such as immune cells to ChP organoids will allow further dissection of different ChP compartments and their cross-talk. ChP organoids will thus be an attractive system to investigate the secretome of different choroidal cells and to identify human-specific and evolutionarily conserved signaling factors. The ChP is also an important contributor to disease. A further translational application will be the generation of ChP organoids from induced pluripotent stem cells from individual patients to investigate links between specific mutations and ChP dysfunction. An exciting next step is to probe the functional implications of ChP epithelial cell hetereogeneity, and of other ChP cell types, including their in vivo distribution and whether there are regional differences between different brain ventricles, which differ in their secretomes ([ 3 ][3]). Choroidal epithelial cells may be specialized for different functions, given their many roles in vivo, and use different modes of secretion. The challenge now is to unravel how the functions of each choroidal cell type are regulated by different inputs to the ChP. Indeed, the ChP lies at the interface of blood and the central nervous system and is therefore singularly poised to sense and integrate signals from the periphery as well as the brain and to dynamically adapt its secretome in different physiological states of homeostasis and disease. It is an exciting time in the field to discover how this system is orchestrated and dynamically participates in brain function. 1. [↵][12]1. J. F. Ghersi-Egea et al ., Acta Neuropathol. 135, 337 (2018). [OpenUrl][13][CrossRef][14][PubMed][15] 2. [↵][16]1. L. Pellegrini et al ., Science 369, eaaz5626 (2020). [OpenUrl][17][Abstract/FREE Full Text][18] 3. [↵][19]1. R. M. Fame, 2. M. K. Lehtinen , Dev. Cell 52, 261 (2020). [OpenUrl][20][CrossRef][21][PubMed][22] 4. [↵][23]1. F. Marques et al ., Neurobiol. Dis. 107, 32 (2017). [OpenUrl][24] 5. [↵][25]1. V. Silva-Vargas et al ., Cell Stem Cell 19, 643 (2016). [OpenUrl][26][CrossRef][27][PubMed][28] 6. 1. M. K. Lehtinen et al ., Neuron 69, 893 (2011). [OpenUrl][29][CrossRef][30][PubMed][31][Web of Science][32] 7. 1. K. Baruch et al ., Science 346, 89 (2014). [OpenUrl][33][Abstract/FREE Full Text][34] 8. [↵][35]1. J. Myung et al ., Nat. Commun. 9, 1062 (2018). [OpenUrl][36][CrossRef][37] 9. [↵][38]1. N. R. Saunders, 2. K. M. Dziegielewska, 3. K. Møllgård, 4. M. D. Habgood , J. Physiol. 596, 5723 (2018). [OpenUrl][39][CrossRef][40] 10. [↵][41]1. T. Takebe, 2. J. M. Wells , Science 364, 956 (2019). [OpenUrl][42][Abstract/FREE Full Text][43] 11. [↵][44]1. H. Sakaguchi et al ., Nat. Commun. 6, 8896 (2015). [OpenUrl][45][CrossRef][46][PubMed][47] 12. [↵][48]1. G. J. Dohrmann, 2. P. C. Bucy , J. Neurosurg. 33, 506 (1970). [OpenUrl][49][CrossRef][50][PubMed][51][Web of Science][52] Acknowledgments: F. D. is supported by European Research Council (ERC) Advanced Grant NeuroStemCircuit, Swiss National Science Foundation Grant 31003A_163088, and the University of Basel. We thank D. Thaler for comments. [1]: #ref-1 [2]: #ref-2 [3]: #ref-3 [4]: #ref-4 [5]: #ref-5 [6]: #ref-8 [7]: #ref-9 [8]: pending:yes [9]: #ref-10 [10]: #ref-11 [11]: #ref-12 [12]: #xref-ref-1-1 "View reference 1 in text" [13]: {openurl}?query=rft.jtitle%253DActa%2BNeuropathol.%26rft.volume%253D135%26rft.spage%253D337%26rft_id%253Dinfo%253Adoi%252F10.1007%252Fs00401-018-1807-1%26rft_id%253Dinfo%253Apmid%252F29368213%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [14]: /lookup/external-ref?access_num=10.1007/s00401-018-1807-1&link_type=DOI [15]: /lookup/external-ref?access_num=29368213&link_type=MED&atom=%2Fsci%2F369%2F6500%2F143.atom [16]: #xref-ref-2-1 "View reference 2 in text" [17]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DPellegrini%26rft.auinit1%253DL.%26rft.volume%253D369%26rft.issue%253D6500%26rft.spage%253Deaaz5626%26rft.epage%253Deaaz5626%26rft.atitle%253DHuman%2BCNS%2Bbarrier-forming%2Borganoids%2Bwith%2Bcerebrospinal%2Bfluid%2Bproduction%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.aaz5626%26rft_id%253Dinfo%253Apmid%252F32527923%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [18]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjE3OiIzNjkvNjUwMC9lYWF6NTYyNiI7czo0OiJhdG9tIjtzOjIyOiIvc2NpLzM2OS82NTAwLzE0My5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [19]: #xref-ref-3-1 "View reference 3 in text" [20]: {openurl}?query=rft.jtitle%253DDev.%2BCell%26rft.volume%253D52%26rft.spage%253D261%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.devcel.2020.01.027%26rft_id%253Dinfo%253Apmid%252F32049038%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [21]: /lookup/external-ref?access_num=10.1016/j.devcel.2020.01.027&link_type=DOI [22]: /lookup/external-ref?access_num=32049038&link_type=MED&atom=%2Fsci%2F369%2F6500%2F143.atom [23]: #xref-ref-4-1 "View reference 4 in text" [24]: {openurl}?query=rft.jtitle%253DNeurobiol.%2BDis.%26rft.volume%253D107%26rft.spage%253D32%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [25]: #xref-ref-5-1 "View reference 5 in text" [26]: {openurl}?query=rft.jtitle%253DCell%2BStem%2BCell%26rft.volume%253D19%26rft.spage%253D643%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.stem.2016.06.013%26rft_id%253Dinfo%253Apmid%252F27452173%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [27]: /lookup/external-ref?access_num=10.1016/j.stem.2016.06.013&link_type=DOI [28]: /lookup/external-ref?access_num=27452173&link_type=MED&atom=%2Fsci%2F369%2F6500%2F143.atom [29]: {openurl}?query=rft.jtitle%253DNeuron%26rft.volume%253D69%26rft.spage%253D893%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.neuron.2011.01.023%26rft_id%253Dinfo%253Apmid%252F21382550%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [30]: /lookup/external-ref?access_num=10.1016/j.neuron.2011.01.023&link_type=DOI [31]: /lookup/external-ref?access_num=21382550&link_type=MED&atom=%2Fsci%2F369%2F6500%2F143.atom [32]: /lookup/external-ref?access_num=000288736500008&link_type=ISI [33]: {openurl}?query=rft.jtitle%253DScience%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.1252945%26rft_id%253Dinfo%253Apmid%252F25147279%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [34]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjExOiIzNDYvNjIwNS84OSI7czo0OiJhdG9tIjtzOjIyOiIvc2NpLzM2OS82NTAwLzE0My5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30= [35]: #xref-ref-8-1 "View reference 8 in text" [36]: {openurl}?query=rft.jtitle%253DNat.%2BCommun.%26rft.volume%253D9%26rft.spage%253D1062%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fs41467-018-03507-2%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [37]: /lookup/external-ref?access_num=10.1038/s41467-018-03507-2&link_type=DOI [38]: #xref-ref-9-1 "View reference 9 in text" [39]: {openurl}?query=rft.jtitle%253DJ.%2BPhysiol.%26rft.volume%253D596%26rft.spage%253D5723%26rft_id%253Dinfo%253Adoi%252F10.1113%252FJP275376%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [40]: /lookup/external-ref?access_num=10.1113/JP275376&link_type=DOI [41]: #xref-ref-10-1 "View reference 10 in text" [42]: {openurl}?query=rft.jtitle%253DScience%26rft.stitle%253DScience%26rft.aulast%253DTakebe%26rft.auinit1%253DT.%26rft.volume%253D364%26rft.issue%253D6444%26rft.spage%253D956%26rft.epage%253D959%26rft.atitle%253DOrganoids%2Bby%2Bdesign%26rft_id%253Dinfo%253Adoi%252F10.1126%252Fscience.aaw7567%26rft_id%253Dinfo%253Apmid%252F31171692%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [43]: /lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIzNjQvNjQ0NC85NTYiO3M6NDoiYXRvbSI7czoyMjoiL3NjaS8zNjkvNjUwMC8xNDMuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9 [44]: #xref-ref-11-1 "View reference 11 in text" [45]: {openurl}?query=rft.jtitle%253DNat.%2BCommun.%26rft.volume%253D6%26rft.spage%253D8896%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fncomms9896%26rft_id%253Dinfo%253Apmid%252F26573335%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [46]: /lookup/external-ref?access_num=10.1038/ncomms9896&link_type=DOI [47]: /lookup/external-ref?access_num=26573335&link_type=MED&atom=%2Fsci%2F369%2F6500%2F143.atom [48]: #xref-ref-12-1 "View reference 12 in text" [49]: {openurl}?query=rft.jtitle%253DJournal%2Bof%2Bneurosurgery%26rft.stitle%253DJ%2BNeurosurg%26rft.aulast%253DDohrmann%26rft.auinit1%253DG.%2BJ.%26rft.volume%253D33%26rft.issue%253D5%26rft.spage%253D506%26rft.epage%253D516%26rft.atitle%253DHuman%2Bchoroid%2Bplexus%253A%2Ba%2Blight%2Band%2Belectron%2Bmicroscopic%2Bstudy.%26rft_id%253Dinfo%253Adoi%252F10.3171%252Fjns.1970.33.5.0506%26rft_id%253Dinfo%253Apmid%252F4920907%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [50]: /lookup/external-ref?access_num=10.3171/jns.1970.33.5.0506&link_type=DOI [51]: /lookup/external-ref?access_num=4920907&link_type=MED&atom=%2Fsci%2F369%2F6500%2F143.atom [52]: /lookup/external-ref?access_num=A1970H758200004&link_type=ISI
领域	气候变化 ; 资源环境
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引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/283385
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Violeta Silva-Vargas,Fiona Doetsch. Exploring the source of human brain fluids[J]. Science,2020.
APA	Violeta Silva-Vargas,&Fiona Doetsch.(2020).Exploring the source of human brain fluids.Science.
MLA	Violeta Silva-Vargas,et al."Exploring the source of human brain fluids".Science (2020).