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      Hypoxia-enhanced Blood-Brain Barrier Chip recapitulates human barrier function and shuttling of drugs and antibodies

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          Abstract

          The high selectivity of the human blood-brain barrier (BBB) restricts delivery of many pharmaceuticals and therapeutic antibodies to the central nervous system. Here, we describe an in vitro microfluidic organ-on-a-chip BBB model lined by induced pluripotent stem cell-derived human brain microvascular endothelium interfaced with primary human brain astrocytes and pericytes that recapitulates the high level of barrier function of the in vivo human BBB for at least one week in culture. The endothelium expresses high levels of tight junction proteins and functional efflux pumps, and it displays selective transcytosis of peptides and antibodies previously observed in vivo. Increased barrier functionality was accomplished using a developmentally-inspired induction protocol that includes a period of differentiation under hypoxic conditions. This enhanced BBB Chip may therefore represent a new in vitro tool for development and validation of delivery systems that transport drugs and therapeutic antibodies across the human BBB.

          Abstract

          In vitro blood-brain barrier (BBB) models do not fully recapitulate the in vivo barrier function. Here the authors develop an organ-on-a-chip BBB model using iPS-derived human brain endothelial cells differentiated under hypoxia, primary human pericytes and astrocytes, which maintains in vivo-like BBB barrier and shuttling functions for a week.

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          Most cited references 58

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          Involvement of the low-density lipoprotein receptor-related protein in the transcytosis of the brain delivery vector angiopep-2.

          The blood-brain barrier (BBB) restricts the entry of proteins as well as potential drugs to cerebral tissues. We previously reported that a family of Kunitz domain-derived peptides called Angiopeps can be used as a drug delivery system for the brain. Here, we further characterize the transcytosis ability of these peptides using an in vitro model of the BBB and in situ brain perfusion. These peptides, and in particular Angiopep-2, exhibited higher transcytosis capacity and parenchymal accumulation than do transferrin, lactoferrin, and avidin. Angiopep-2 transport and accumulation in brain endothelial cells were unaffected by the P-glycoprotein inhibitor, cyclosporin A, indicating that this peptide is not a substrate for the efflux pump P-glycoprotein. However, competition studies show that activated alpha(2)-macroglobulin, a specific ligand for the low-density lipoprotein receptor-related protein-1 (LRP1) and Angiopep-2 can share the same receptor. In addition, LRP1 was detected in glioblastomas and brain metastases from lung and skin cancers. Fluorescent microscopy also revealed that Alexa488-Angiopep-2 co-localized with LRP1 in brain endothelial cell monolayers. Overall, these results suggest that Angiopep-2 transport across the BBB is, in part, mediated by LRP1.
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            Blood-brain barrier active efflux transporters: ATP-binding cassette gene family.

            The blood-brain barrier (BBB) contributes to brain homeostasis by protecting the brain from potentially harmful endogenous and exogenous substances. BBB active drug efflux transporters of the ATP-binding cassette (ABC) gene family are increasingly recognized as important determinants of drug distribution to, and elimination from, the CNS. The ABC efflux transporter P-glycoprotein (Pgp) has been demonstrated as a key element of the BBB that can actively transport a huge variety of lipophilic drugs out of the brain capillary endothelial cells that form the BBB. In addition to Pgp, other ABC efflux transporters such as members of the multidrug resistance protein (MRP) family and breast cancer resistance protein (BCRP) seem to contribute to BBB function. Consequences of ABC efflux transporters in the BBB include minimizing or avoiding neurotoxic adverse effects of drugs that otherwise would penetrate into the brain. However, ABC efflux transporters may also limit the central distribution of drugs that are beneficial to treat CNS diseases. Furthermore, neurological disorders such as epilepsy may be associated with overexpression of ABC efflux transporters at the BBB, resulting in pharmacoresistance to therapeutic medication. Therefore, modulation of ABC efflux transporters at the BBB forms a novel strategy to enhance the penetration of drugs into the brain and may yield new therapeutic options for drug-resistant CNS diseases.
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              Overview and introduction: the blood-brain barrier in health and disease.

              This article introduces the special issue on "Blood-Brain Barrier and Epilepsy." We review briefly current understanding of the structure and function of the blood-brain barrier (BBB), including its development and normal physiology, and ways in which it can be affected in pathology. The BBB formed by the endothelium of cerebral blood vessels is one of three main barrier sites protecting the central nervous system (CNS). The barrier is not a rigid structure, but a dynamic interface with a range of interrelated functions, resulting from extremely effective tight junctions, transendothelial transport systems, enzymes, and regulation of leukocyte permeation, which thereby generates the physical, transport, enzymatic, and immune regulatory functions of the BBB. The brain endothelial cells are important components of a "modular" structure, the neurovascular unit (NVU), with several associated cell types and extracellular matrix components. Modern methods have helped in identifying a range of proteins involved in barrier structure and function, and recent studies have revealed important stages, cell types, and signaling pathways important in BBB development. There is a growing list of CNS pathologies showing BBB dysfunction, with strong evidence that this can play a major role in certain disease etiologies. The articles that follow in this issue summarize in more detail reports and discussions of the recent international meeting on "BBB in Neurological Dysfunctions," which took place recently at Ben-Gurion University of the Negev Desert Campus (Beer-Sheva, Israel), focusing on the link between experimental and clinical studies, and the ways in which these lead to improved drug treatments. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.
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                Author and article information

                Contributors
                don.ingber@wyss.harvard.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                13 June 2019
                13 June 2019
                2019
                : 10
                Affiliations
                [1 ]ISNI 000000041936754X, GRID grid.38142.3c, Wyss Institute for Biologically Inspired Engineering at Harvard University, ; Boston, MA 02115 USA
                [2 ]ISNI 0000 0004 0378 8438, GRID grid.2515.3, Department of Neurosurgery, , Boston Children’s Hospital and Harvard Medical School, ; Boston, MA 02115 USA
                [3 ]ISNI 0000 0001 2167 3675, GRID grid.14003.36, Department of Chemical and Biological Engineering, , University of Wisconsin-Madison, ; Madison, WI 53706 USA
                [4 ]ISNI 000000041936754X, GRID grid.38142.3c, Harvard John A. Paulson School of Engineering and Applied Sciences, , Harvard University, ; Cambridge, MA 02138 USA
                [5 ]ISNI 0000 0004 0378 8438, GRID grid.2515.3, Vascular Biology Program and Department of Surgery, , Boston Children’s Hospital and Harvard Medical School, ; Boston, MA 02115 USA
                [6 ]ISNI 0000 0004 0381 814X, GRID grid.42687.3f, Present Address: Ulsan National Institute of Science and Technology (UNIST), ; UNIST-gil 50, Ulsan, 44919 Republic of Korea
                [7 ]ISNI 0000000121581746, GRID grid.5037.1, Division of Micro and Nanosystems, , KTH Royal Institute of Technology, ; Stockholm, Sweden
                [8 ]ISNI 0000 0004 1937 0626, GRID grid.4714.6, Swedish Medical Nanoscience Center, Department of Neuroscience, , Karolinska Institute, ; Stockholm, Sweden
                Article
                10588
                10.1038/s41467-019-10588-0
                6565686
                31197168
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef https://doi.org/10.13039/501100003725, National Research Foundation of Korea (NRF);
                Award ID: NRF-2018R1A5A1024340
                Award ID: 2018K1A4A3A01063890
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/501100004063, Knut och Alice Wallenbergs Stiftelse (Knut and Alice Wallenberg Foundation);
                Award ID: WAF 2015-0178
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100000185, United States Department of Defense | Defense Advanced Research Projects Agency (DARPA);
                Award ID: W911NF-12-2-0036
                Award Recipient :
                Categories
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                Custom metadata
                © The Author(s) 2019

                Uncategorized

                biological techniques, neuroscience, drug discovery, biotechnology, stem cells

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