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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 references56

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          Interleukin-6, a Major Cytokine in the Central Nervous System

          Interleukin-6 (IL-6) is a cytokine originally identified almost 30 years ago as a B-cell differentiation factor, capable of inducing the maturation of B cells into antibody-producing cells. As with many other cytokines, it was soon realized that IL-6 was not a factor only involved in the immune response, but with many critical roles in major physiological systems including the nervous system. IL-6 is now known to participate in neurogenesis (influencing both neurons and glial cells), and in the response of mature neurons and glial cells in normal conditions and following a wide arrange of injury models. In many respects, IL-6 behaves in a neurotrophin-like fashion, and seemingly makes understandable why the cytokine family that it belongs to is known as neuropoietins. Its expression is affected in several of the main brain diseases, and animal models strongly suggest that IL-6 could have a role in the observed neuropathology and that therefore it is a clear target of strategic therapies.
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            Inflammation in Alzheimer disease: driving force, bystander or beneficial response?

            Alzheimer disease is a progressive dementia with unknown etiology that affects a growing number of the aging population. Increased expression of inflammatory mediators in postmortem brains of people with Alzheimer disease has been reported, and epidemiological studies link the use of anti-inflammatory drugs with reduced risk for the disorder. On the initial basis of this kind of evidence, inflammation has been proposed as a possible cause or driving force of Alzheimer disease. If true, this could have important implications for the development of new treatments. Alternatively, inflammation could simply be a byproduct of the disease process and may not substantially alter its course. Or components of the inflammatory response might even be beneficial and slow the disease. To address these possibilities, we need to determine whether inflammation in Alzheimer disease is an early event, whether it is genetically linked with the disease and whether manipulation of inflammatory pathways changes the course of the pathology. Although there is still little evidence that inflammation triggers or promotes Alzheimer disease, increasing evidence from mouse models suggests that certain inflammatory mediators are potent drivers of the disease. Related factors, on the other hand, elicit beneficial responses and can reduce disease.
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              Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization.

              The extracellular matrix (ECM) is critical for all aspects of vascular biology. In concert with supporting cells, endothelial cells (ECs) assemble a laminin-rich basement membrane matrix that provides structural and organizational stability. During the onset of angiogenesis, this basement membrane matrix is degraded by proteinases, among which membrane-type matrix metalloproteinases (MT-MMPs) are particularly significant. As angiogenesis proceeds, ECM serves essential functions in supporting key signaling events involved in regulating EC migration, invasion, proliferation, and survival. Moreover, the provisional ECM serves as a pliable scaffold wherein mechanical guidance forces are established among distal ECs, thereby providing organizational cues in the absence of cell-cell contact. Finally, through specific integrin-dependent signal transduction pathways, ECM controls the EC cytoskeleton to orchestrate the complex process of vascular morphogenesis by which proliferating ECs organize into multicellular tubes with functional lumens. Thus, the composition of ECM and therefore the regulation of ECM degradation and remodeling serves pivotally in the control of lumen and tube formation and, finally, neovessel stability and maturation.
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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.

                Article
                PONE-D-15-46349
                10.1371/journal.pone.0150360
                4773137
                26930059
                e4782928-212c-4309-b85f-03ff5d2df810
                © 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.

                Page count
                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
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