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      Distinct Contributions of Astrocytes and Pericytes to Neuroinflammation Identified in a 3D Human Blood-Brain Barrier on a Chip

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          Abstract

          Neurovascular inflammation is a major contributor to many neurological disorders, but modeling these processes in vitro has proven to be difficult. Here, we microengineered a three-dimensional (3D) model of the human blood-brain barrier (BBB) within a microfluidic chip by creating a cylindrical collagen gel containing a central hollow lumen inside a microchannel, culturing primary human brain microvascular endothelial cells on the gel’s inner surface, and flowing medium through the lumen. Studies were carried out with the engineered microvessel containing endothelium in the presence or absence of either primary human brain pericytes beneath the endothelium or primary human brain astrocytes within the surrounding collagen gel to explore the ability of this simplified model to identify distinct contributions of these supporting cells to the neuroinflammatory response. This human 3D BBB-on-a-chip exhibited barrier permeability similar to that observed in other in vitro BBB models created with non-human cells, and when stimulated with the inflammatory trigger, tumor necrosis factor-alpha (TNF-α), different secretion profiles for granulocyte colony-stimulating factor (G-CSF) and interleukin-6 (IL-6) were observed depending on the presence of astrocytes or pericytes. Importantly, the levels of these responses detected in the 3D BBB chip were significantly greater than when the same cells were co-cultured in static Transwell plates. Thus, as G-CSF and IL-6 have been reported to play important roles in neuroprotection and neuroactivation in vivo, this 3D BBB chip potentially offers a new method to study human neurovascular function and inflammation in vitro, and to identify physiological contributions of individual cell types.

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          Most cited references 73

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          Astrocyte-endothelial interactions at the blood-brain barrier.

          The blood-brain barrier, which is formed by the endothelial cells that line cerebral microvessels, has an important role in maintaining a precisely regulated microenvironment for reliable neuronal signalling. At present, there is great interest in the association of brain microvessels, astrocytes and neurons to form functional 'neurovascular units', and recent studies have highlighted the importance of brain endothelial cells in this modular organization. Here, we explore specific interactions between the brain endothelium, astrocytes and neurons that may regulate blood-brain barrier function. An understanding of how these interactions are disturbed in pathological conditions could lead to the development of new protective and restorative therapies.
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            Structure and function of the blood-brain barrier.

            Neural signalling within the central nervous system (CNS) requires a highly controlled microenvironment. Cells at three key interfaces form barriers between the blood and the CNS: the blood-brain barrier (BBB), blood-CSF barrier and the arachnoid barrier. The BBB at the level of brain microvessel endothelium is the major site of blood-CNS exchange. The structure and function of the BBB is summarised, the physical barrier formed by the endothelial tight junctions, and the transport barrier resulting from membrane transporters and vesicular mechanisms. The roles of associated cells are outlined, especially the endfeet of astrocytic glial cells, and pericytes and microglia. The embryonic development of the BBB, and changes in pathology are described. The BBB is subject to short and long-term regulation, which may be disturbed in pathology. Any programme for drug discovery or delivery, to target or avoid the CNS, needs to consider the special features of the BBB.
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              Pericytes regulate the blood-brain barrier.

              The blood-brain barrier (BBB) consists of specific physical barriers, enzymes and transporters, which together maintain the necessary extracellular environment of the central nervous system (CNS). The main physical barrier is found in the CNS endothelial cell, and depends on continuous complexes of tight junctions combined with reduced vesicular transport. Other possible constituents of the BBB include extracellular matrix, astrocytes and pericytes, but the relative contribution of these different components to the BBB remains largely unknown. Here we demonstrate a direct role of pericytes at the BBB in vivo. Using a set of adult viable pericyte-deficient mouse mutants we show that pericyte deficiency increases the permeability of the BBB to water and a range of low-molecular-mass and high-molecular-mass tracers. The increased permeability occurs by endothelial transcytosis, a process that is rapidly arrested by the drug imatinib. Furthermore, we show that pericytes function at the BBB in at least two ways: by regulating BBB-specific gene expression patterns in endothelial cells, and by inducing polarization of astrocyte end-feet surrounding CNS blood vessels. Our results indicate a novel and critical role for pericytes in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the BBB.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                1 March 2016
                2016
                : 11
                : 3
                Affiliations
                [1 ]Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, United States of America
                [2 ]Harvard John A. Paulson School of Engineering and Applied Sciences, Cambridge, Massachusetts, United States of America
                [3 ]Department of Pathology, Harvard Medical School, Boston, Massachusetts, United States of America
                [4 ]Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Boston, Massachusetts, United States of America
                Hungarian Academy of Sciences, HUNGARY
                Author notes

                Competing Interests: DEI is a founder and holds equity in Emulate, Inc., and chairs its scientific advisory board. AvdM is a consultant for Emulate, Inc. and receives compensation for these services. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: AH ADvdM EAF JJFS DEI. Performed the experiments: AH ADvdM EAF TEP JJFS. Analyzed the data: AH ADvdM EAF TEP JJFS. Wrote the paper: AH ADvdM EAF TEP JJFS DEI.

                PONE-D-15-46349
                10.1371/journal.pone.0150360
                4773137
                26930059
                © 2016 Herland et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Counts
                Figures: 5, Tables: 0, Pages: 21
                Product
                Funding
                This work was supported by the Defense Advanced Research Projects Agency under Cooperative Agreement Number W911NF-12-2-0036 and the Wyss Institute for Biologically Inspired Engineering at Harvard University. The content of the information does not necessarily reflect the position or the policy of the Defense Advanced Research Projects Agency or the U.S. Government and no official endorsement should be inferred. Additional funding was provided by Sverige-Amerika Stiftelsen [ http://sweamfo.se], Carl Trygger Stiftelse [ http://www.carltryggersstiftelse.se], Erik och Edith Fernstrom’s stiftelse [ https://internwebben.ki.se/en/erik-and-edith-fernstrom-foundation-medical-research] (AH) and KTH opportunities fund [ https://www.kth.se/en/opportunities] (EAF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Glial Cells
                Macroglial Cells
                Astrocytes
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Pericytes
                Biology and Life Sciences
                Biochemistry
                Proteins
                Collagens
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Epithelial Cells
                Endothelial Cells
                Biology and Life Sciences
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                Biological Tissue
                Epithelium
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                All relevant data are within the paper and its Supporting Information files.

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