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      Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration

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          Abstract

          Innate immune cells recruited to inflammatory sites have short life spans and originate from the marrow, which is distributed throughout the long and flat bones. While bone marrow production and release of leukocyte increases after stroke, it is currently unknown if its activity rises homogeneously throughout the entire hematopoietic system. To address this question, we employed spectrally resolved in vivo cell labeling in the murine skull and tibia. We show that in murine models of stroke and aseptic meningitis, skull bone marrow derived neutrophils are more likely to migrate to the adjacent brain tissue than cells that reside in the tibia. Confocal microscopy of the skull-dura interface revealed myeloid cell migration through microscopic vascular channels crossing the inner skull cortex. These observations point to a direct local interaction between the brain and the skull bone marrow through the meninges.

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          Most cited references29

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          Distinct bone marrow blood vessels differentially regulate hematopoiesis

          Bone marrow (BM) endothelial cells (BMECs) form a network of blood vessels (BVs) which regulate both leukocyte trafficking and hematopoietic stem and progenitor cell (HSPC) maintenance. However, it is not clear how BMECs balance these dual roles and if these events occur at the same vascular site. We found that BM stem cell maintenance and leukocyte trafficking are regulated by distinct BV types with different permeability properties. Less permeable arterial BVs maintain HSCs in a low reactive oxygen species (ROS) state, whereas the more permeable sinusoids promote HSPC activation and are the exclusive site for immature and mature leukocyte trafficking to and from the BM. A functional consequence of high BVs permeability is that exposure to blood plasma increases BM HSPC ROS levels, augmenting their migration capacity while compromising their long term repopulation and survival potential. These findings may have relevance for clinical hematopoietic stem cell transplantation and mobilization protocols.
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            Targeting neutrophils in ischemic stroke: translational insights from experimental studies.

            Neutrophils have key roles in ischemic brain injury, thrombosis, and atherosclerosis. As such, neutrophils are of great interest as targets to treat and prevent ischemic stroke. After stroke, neutrophils respond rapidly promoting blood-brain barrier disruption, cerebral edema, and brain injury. A surge of neutrophil-derived reactive oxygen species, proteases, and cytokines are released as neutrophils interact with cerebral endothelium. Neutrophils also are linked to the major processes that cause ischemic stroke, thrombosis, and atherosclerosis. Thrombosis is promoted through interactions with platelets, clotting factors, and release of prothrombotic molecules. In atherosclerosis, neutrophils promote plaque formation and rupture by generating oxidized-low density lipoprotein, enhancing monocyte infiltration, and degrading the fibrous cap. In experimental studies targeting neutrophils can improve stroke. However, early human studies have been met with challenges, and suggest that selective targeting of neutrophils may be required. Several properties of neutrophil are beneficial and thus may important to preserve in patients with stroke including antimicrobial, antiinflammatory, and neuroprotective functions.
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              Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions.

              The tissues of the central nervous system are effectively shielded from the blood circulation by specialized vessels that are impermeable not only to cells, but also to most macromolecules circulating in the blood. Despite this seemingly absolute seclusion, central nervous system tissues are subject to immune surveillance and are vulnerable to autoimmune attacks. Using intravital two-photon imaging in a Lewis rat model of experimental autoimmune encephalomyelitis, here we present in real-time the interactive processes between effector T cells and cerebral structures from their first arrival to manifest autoimmune disease. We observed that incoming effector T cells successively scanned three planes. The T cells got arrested to leptomeningeal vessels and immediately monitored the luminal surface, crawling preferentially against the blood flow. After diapedesis, the cells continued their scan on the abluminal vascular surface and the underlying leptomeningeal (pial) membrane. There, the T cells encountered phagocytes that effectively present antigens, foreign as well as myelin proteins. These contacts stimulated the effector T cells to produce pro-inflammatory mediators, and provided a trigger to tissue invasion and the formation of inflammatory infiltrations.
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                Author and article information

                Journal
                9809671
                21092
                Nat Neurosci
                Nat. Neurosci.
                Nature neuroscience
                1097-6256
                1546-1726
                24 July 2018
                27 August 2018
                September 2018
                27 February 2019
                : 21
                : 9
                : 1209-1217
                Affiliations
                [1 ]Center for Systems Biology, Department of Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
                [2 ]Molecular Imaging and Neurovascular Research Laboratory, Department of Neurology, Dongguk University College of Medicine, Goyang, South Korea
                [3 ]Department of Systems Biology, Harvard Medical School, Boston, Massachusetts, USA
                [4 ]Stroke and Neurovascular Regulation Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital and Harvard Medical School, 149 13 th Street, Boston, Massachusetts, USA.
                [5 ]Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
                Author notes

                Author contributions: F.H. conceived the study, designed, performed and analyzed most experiments and contributed to writing the manuscript. V.F., G.C., D.R., Y.S., K.V., G.R.W., J. K., C.V. and G.S.M. performed flow cytometry and imaging experiments. D.E.K., R.W., F.K.S. and M.A.M. discussed and interpreted data, provided strategic input, raised funding and edited the manuscript. M.N. supervised the study and wrote the manuscript with input from all authors.

                Corresponding author: Matthias Nahrendorf, Center for Systems Biology, 185 Cambridge Street, Boston, MA 02114, Tel: (617) 935-9177, Fax: (617) 643-6133, mnahrendorf@ 123456mgh.harvard.edu
                Article
                NIHMS1500752
                10.1038/s41593-018-0213-2
                6148759
                30150661
                db91deb9-0e17-4ade-b28f-1cf8cb287445

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